http://www.mdpi.com/journal/viruses Latest open access articles published in Viruses at http://www.mdpi.com/journal/viruses/ http://www.mdpi.com/1999-4915/4/2/276/ I wish to express concern about the maintenance of laboratory strains of H5N1 influenza viruses that might be adapted for transmission among humans. http://www.mdpi.com/1999-4915/4/2/276/ Tue, 07 Feb 2012 00:00:00 CET Viruses 2012-02-07 4 2 Editorial 276 279 1999-4915 A Plea for Caution: Huge Risks Associated with Lab-bred Flu 2012-02-07 doi: 10.3390/v4020276 Viktor Müller http://www.mdpi.com/1999-4915/4/2/258/ Ebolavirus (EBOV) and Marburgvirus (MARV) that compose the filovirus family of negative strand RNA viruses infect a broad range of mammalian cells. Recent studies indicate that cellular entry of this family of viruses requires a series of cellular protein interactions and molecular mechanisms, some of which are unique to filoviruses and others are commonly used by all viral glycoproteins. Details of this entry pathway are highlighted here. Virus entry into cells is initiated by the interaction of the viral glycoprotein1 subunit (GP1) with both adherence factors and one or more receptors on the surface of host cells. On epithelial cells, we recently demonstrated that TIM-1 serves as a receptor for this family of viruses, but the cell surface receptors in other cell types remain unidentified. Upon receptor binding, the virus is internalized into endosomes primarily via macropinocytosis, but perhaps by other mechanisms as well. Within the acidified endosome, the heavily glycosylated GP1 is cleaved to a smaller form by the low pH-dependent cellular proteases Cathepsin L and B, exposing residues in the receptor binding site (RBS). Details of the molecular events following cathepsin-dependent trimming of GP1 are currently incomplete; however, the processed GP1 specifically interacts with endosomal/lysosomal membranes that contain the Niemann Pick C1 (NPC1) protein and expression of NPC1 is required for productive infection, suggesting that GP/NPC1 interactions may be an important late step in the entry process. Additional events such as further GP1 processing and/or reducing events may also be required to generate a fusion-ready form of the glycoprotein. Once this has been achieved, sequences in the filovirus GP2 subunit mediate viral/cellular membrane fusion via mechanisms similar to those previously described for other enveloped viruses. This multi-step entry pathway highlights the complex and highly orchestrated path of internalization and fusion that appears unique for filoviruses. http://www.mdpi.com/1999-4915/4/2/258/ Tue, 07 Feb 2012 00:00:00 CET Viruses 2012-02-07 4 2 Review 258 275 1999-4915 Filovirus Entry: A Novelty in the Viral Fusion World 2012-02-07 doi: 10.3390/v4020258 Catherine L. Hunt Nicholas J. Lennemann Wendy Maury http://www.mdpi.com/1999-4915/4/2/236/ The domestic cat is afflicted with multiple viruses that serve as powerful models for human disease including cancers, SARS and HIV/AIDS. Cat viruses that cause these diseases have been studied for decades revealing detailed insight concerning transmission, virulence, origins and pathogenesis. Here we review recent genetic advances that have questioned traditional wisdom regarding the origins of virulent Feline infectious peritonitis (FIP) diseases, the pathogenic potential of Feline Immunodeficiency Virus (FIV) in wild non-domestic Felidae species, and the restriction of Feline Leukemia Virus (FeLV) mediated immune impairment to domestic cats rather than other Felidae species. The most recent interpretations indicate important new evolutionary conclusions implicating these deadly infectious agents in domestic and non-domestic felids. http://www.mdpi.com/1999-4915/4/2/236/ Tue, 07 Feb 2012 00:00:00 CET Viruses 2012-02-07 4 2 Review 236 257 1999-4915 Emerging Viruses in the Felidae: Shifting Paradigms 2012-02-07 doi: 10.3390/v4020236 Stephen J. O’Brien Jennifer L. Troyer Meredith A. Brown Warren E. Johnson Agostinho Antunes Melody E. Roelke Jill Pecon-Slattery http://www.mdpi.com/1999-4915/4/2/211/ Bacterial artificial chromosome (BAC) vectors were first developed to facilitate the propagation and manipulation of large DNA fragments in molecular biology studies for uses such as genome sequencing projects and genetic disease models. To facilitate these studies, methodologies have been developed to introduce specific mutations that can be directly applied to the mutagenesis of infectious clones (icBAC) using BAC technologies. This has resulted in rapid identification of gene function and expression at unprecedented rates. Here we review the major developments in BAC mutagenesis in vitro. This review summarises the technologies used to construct and introduce mutations into herpesvirus icBAC. It also explores developing technologies likely to provide the next leap in understanding these important viruses. http://www.mdpi.com/1999-4915/4/2/211/ Fri, 03 Feb 2012 00:00:00 CET Viruses 2012-02-03 4 2 Review 211 235 1999-4915 Back to BAC: The Use of Infectious Clone Technologies for Viral Mutagenesis 2012-02-03 doi: 10.3390/v4020211 Robyn N. Hall Joanne Meers Elizabeth Fowler Timothy Mahony http://www.mdpi.com/1999-4915/4/2/200/ Human rhinovirus (HRV) is a leading cause of acute respiratory infection (ARI) in young children and infants worldwide and has a high impact on morbidity and mortality in this population. Initially, HRV was classified into two species: HRV-A and HRV-B. Recently, a species called HRV-C and possibly another species, HRV-D, were identified. In Mexico, there is little information about the role of HRV as a cause of ARI, and the presence and importance of species such as HRV-C are not known. The aim of this study was to determine the clinical characteristics and genetic variability of HRV in Mexican children. Genetic characterization was carried out by phylogenetic analysis of the 5′-nontranslated region (5′-NTR) of the HRV genome. The results show that the newly identified HRV-C is circulating in Mexican children more frequently than HRV-B but not as frequently as HRV-A, which was the most frequent species. Most of the cases of the three species of HRV were in children under 2 years of age, and all species were associated with very mild and moderate ARI. http://www.mdpi.com/1999-4915/4/2/200/ Wed, 25 Jan 2012 00:00:00 CET Viruses 2012-01-25 4 2 Article 200 210 1999-4915 Clinical Characteristics and Genetic Variability of Human Rhinovirus in Mexico 2012-01-25 doi: 10.3390/v4020200 Adriana Landa-Cardeña Jaime Morales-Romero Rebeca García-Roman Ana Georgina Cobián-Güemes Ernesto Méndez Cristina Ortiz-Leon Felipe Pitalúa-Cortés Silvia Ivonne Mora Hilda Montero http://www.mdpi.com/1999-4915/4/1/184/ Single cycle reporter viruses that preserve the majority of the HIV-1 genome, long terminal repeat-promoted transcription and Rev-dependent structural protein expression are useful for investigating the viral life cycle. Reporter viruses that encode the viral proteins in cis in this way have been lacking for feline immunodeficiency virus (FIV), where the field has used genetically minimized transfer vectors with viral proteins supplied in trans. Here we report construction and use of a panel of single cycle FIV reporter viruses that express fluorescent protein markers. The viruses can be produced to high titer using human cell transfection and can transduce diverse target cells. To illustrate utility, we tested versions that are (+) and (-) for OrfA, an FIV accessory protein required for replication in primary lymphocytes and previously implicated in down-regulation of the primary FIV entry receptor CD134. We observed CD134 down-regulation after infection with or without OrfA, and equivalent virion production as well. These results suggest a role for FIV proteins besides Env or OrfA in CD134 down-regulation. http://www.mdpi.com/1999-4915/4/1/184/ Mon, 23 Jan 2012 00:00:00 CET Viruses 2012-01-23 4 1 Article 184 199 1999-4915 Construction and Testing of orfA +/- FIV Reporter Viruses 2012-01-23 doi: 10.3390/v4010184 Hind J. Fadel Dyana T. Saenz Eric M. Poeschla http://www.mdpi.com/1999-4915/4/1/167/ Outbreaks of the southern rice black-streaked dwarf virus (SRBSDV) have caused significant crop losses in southern China in recent years, especially in 2010. There are no effective, quick and practicable methods for the diagnosis of rice dwarf disease that can be used in the field. Traditional reverse transcription-polymerase chain reaction (RT-PCR) methodology is accurate but requires expensive reagents and instruments, as well as complex procedures that limit its applicability for field tests. To develop a sensitive and reliable assay for routine laboratory diagnosis, a rapid dot enzyme-linked immunosorbent assay (dot-ELISA) method was developed for testing rice plants infected by SRBSDV. Based on anti-SRBSDV rabbit antiserum, this new dot-ELISA was highly reliable, sensitive and specific toward SRBSDV. The accuracy of two blotting media, polyvinylidene fluoride membrane (PVDF membrane) and nitrocellulose filter membrane (NC membrane), was compared. In order to facilitate the on-site diagnosis, three county laboratories were established in Shidian (Yunnan province), Jianghua (Hunan Province) and Libo (Guizhou province). Suspected rice cases from Shidian, Yuanjiang and Malipo in Yunnan province were tested and some determined to be positive for SRBSDV by the dot-ELISA and confirmed by the One Step RT-PCR method. To date, hundreds of suspected rice samples collected from 61 districts in southwestern China have been tested, among which 55 districts were found to have rice crops infected by SRBSDV. Furthermore, the test results in the county laboratories showed that Libo, Dehong (suspected samples were sent to Shidian) and Jianghua were experiencing a current SRBSDV outbreak. http://www.mdpi.com/1999-4915/4/1/167/ Mon, 23 Jan 2012 00:00:00 CET Viruses 2012-01-23 4 1 Article 167 183 1999-4915 The Development and Application of a Dot-ELISA Assay for Diagnosis of Southern Rice Black-Streaked Dwarf Disease in the Field 2012-01-23 doi: 10.3390/v4010167 Zhenchao Wang Dandan Yu Xiangyang Li Mengjiao Zeng Zhuo Chen Liang Bi Jiaju Liu Linhong Jin Deyu Hu Song Yang Baoan Song http://www.mdpi.com/1999-4915/4/1/140/ Members of the family Rhabdoviridae are single-stranded RNA viruses and globally important pathogens of wild and cultured fish and thus relatively well studied in their respective hosts or other model systems. Here, we review the protective immune mechanisms that fish mount in response to rhabdovirus infections. Teleost fish possess the principal components of innate and adaptive immunity found in other vertebrates. Neutralizing antibodies are critical for long-term protection from fish rhabdoviruses, but several studies also indicate a role for cell-mediated immunity. Survival of acute rhabdoviral infection is also dependent on innate immunity, particularly the interferon (IFN) system that is rapidly induced in response to infection. Paradoxically, rhabdoviruses are sensitive to the effects of IFN but virulent rhabdoviruses can continue to replicate owing to the abilities of the matrix (M) protein to mediate host-cell shutoff and the non‑virion (NV) protein to subvert programmed cell death and suppress functional IFN. While many basic features of the fish immune response to rhabdovirus infections are becoming better understood, much less is known about how factors in the environment affect the ecology of rhabdovirus infections in natural populations of aquatic animals. http://www.mdpi.com/1999-4915/4/1/140/ Wed, 18 Jan 2012 00:00:00 CET Viruses 2012-01-18 4 1 Review 140 166 1999-4915 Immunity to Fish Rhabdoviruses 2012-01-18 doi: 10.3390/v4010140 Maureen K. Purcell Kerry J. Laing James R. Winton http://www.mdpi.com/1999-4915/4/1/117/ Rhabdoviruses enter the cell via the endocytic pathway and subsequently fuse with a cellular membrane within the acidic environment of the endosome. Both receptor recognition and membrane fusion are mediated by a single transmembrane viral glycoprotein (G). Fusion is triggered via a low-pH induced structural rearrangement. G is an atypical fusion protein as there is a pH-dependent equilibrium between its pre- and post-fusion conformations. The elucidation of the atomic structures of these two conformations for the vesicular stomatitis virus (VSV) G has revealed that it is different from the previously characterized class I and class II fusion proteins. In this review, the pre- and post-fusion VSV G structures are presented in detail demonstrating that G combines the features of the class I and class II fusion proteins. In addition to these similarities, these G structures also reveal some particularities that expand our understanding of the working of fusion machineries. Combined with data from recent studies that revealed the cellular aspects of the initial stages of rhabdovirus infection, all these data give an integrated view of the entry pathway of rhabdoviruses into their host cell. http://www.mdpi.com/1999-4915/4/1/117/ Wed, 18 Jan 2012 00:00:00 CET Viruses 2012-01-18 4 1 Review 117 139 1999-4915 Molecular and Cellular Aspects of Rhabdovirus Entry 2012-01-18 doi: 10.3390/v4010117 Aurélie A. V. Albertini Eduard Baquero Anna Ferlin Yves Gaudin http://www.mdpi.com/1999-4915/4/1/102/ Porcine reproductive and respiratory syndrome virus (PRRSV) can subvert early innate immunity, which leads to ineffective antimicrobial responses. Overcoming immune subversion is critical for developing vaccines and other measures to control this devastating swine virus. The overall goal of this work was to enhance innate and adaptive immunity following vaccination through the expression of interferon (IFN) genes by the PRRSV genome. We have constructed a series of recombinant PRRS viruses using an infectious PRRSV cDNA clone (pCMV-P129). Coding regions of exogenous genes, which included Renilla luciferase (Rluc), green and red fluorescent proteins (GFP and DsRed, respectively) and several interferons (IFNs), were constructed and expressed through a unique subgenomic mRNA placed between ORF1b and ORF2 of the PRRSV infectious clone. The constructs, which expressed Rluc, GFP, DsRed, efficiently produced progeny viruses and mimicked the parental virus in both MARC-145 cells and porcine macrophages. In contrast, replication of IFN-expressing viruses was attenuated, similar to the level of replication observed after the addition of exogenous IFN. Furthermore, the IFN expressing viruses inhibited the replication of a second PRRS virus co-transfected or co-infected. Inhibition by the different IFN subtypes corresponded to their anti-PRRSV activity, i.e., IFNω5 » IFNα1 > IFN-β > IFNδ3. In summary, the indicator-expressing viruses provided an efficient means for real-time monitoring of viral replication thus allowing high‑throughput elucidation of the role of host factors in PRRSV infection. This was shown when they were used to clearly demonstrate the involvement of tumor susceptibility gene 101 (TSG101) in the early stage of PRRSV infection. In addition, replication‑competent IFN-expressing viruses may be good candidates for development of modified live virus (MLV) vaccines, which are capable of reversing subverted innate immune responses and may induce more effective adaptive immunity against PRRSV infection. http://www.mdpi.com/1999-4915/4/1/102/ Wed, 18 Jan 2012 00:00:00 CET Viruses 2012-01-18 4 1 Article 102 116 1999-4915 Replication-Competent Recombinant Porcine Reproductive and Respiratory Syndrome (PRRS) Viruses Expressing Indicator Proteins and Antiviral Cytokines 2012-01-18 doi: 10.3390/v4010102 Yongming Sang Jishu Shi Wenjing Sang Raymond R. R. Rowland Frank Blecha http://www.mdpi.com/1999-4915/4/1/83/ Arenaviruses comprise a diverse family of enveloped negative-strand RNA viruses that are endemic to specific rodent hosts worldwide. Several arenaviruses cause severe hemorrhagic fevers in humans, including Junín and Machupo viruses in South America and Lassa fever virus in western Africa. Arenavirus entry into the host cell is mediated by the envelope glycoprotein complex, GPC. The virion is endocytosed on binding to a cell-surface receptor, and membrane fusion is initiated in response to physiological acidification of the endosome. As with other class I virus fusion proteins, GPC-mediated membrane fusion is promoted through a regulated sequence of conformational changes leading to formation of the classical postfusion trimer-of-hairpins structure. GPC is, however, unique among the class I fusion proteins in that the mature complex retains a stable signal peptide (SSP) as a third subunit, in addition to the canonical receptor-binding and fusion proteins. We will review the curious properties of the tripartite GPC complex and describe evidence that SSP interacts with the fusion subunit to modulate pH-induced activation of membrane fusion. This unusual solution to maintaining the metastable prefusion state of GPC on the virion and activating the class I fusion cascade at acidic pH provides novel targets for antiviral intervention. http://www.mdpi.com/1999-4915/4/1/83/ Fri, 13 Jan 2012 00:00:00 CET Viruses 2012-01-13 4 1 Review 83 101 1999-4915 The Curious Case of Arenavirus Entry, and Its Inhibition 2012-01-13 doi: 10.3390/v4010083 Jack H. Nunberg Joanne York http://www.mdpi.com/1999-4915/4/1/62/ The development of animal models of dengue virus (DENV) infection and disease has been challenging, as epidemic DENV does not naturally infect non-human species. Non-human primates (NHPs) can sustain viral replication in relevant cell types and develop a robust immune response, but they do not develop overt disease. In contrast, certain immunodeficient mouse models infected with mouse-adapted DENV strains show signs of severe disease similar to the ‘vascular-leak’ syndrome seen in severe dengue in humans. Humanized mouse models can sustain DENV replication and show some signs of disease, but further development is needed to validate the immune response. Classically, immunocompetent mice infected with DENV do not manifest disease or else develop paralysis when inoculated intracranially; however, a new model using high doses of DENV has recently been shown to develop hemorrhagic signs after infection. Overall, each model has its advantages and disadvantages and is differentially suited for studies of dengue pathogenesis and immunopathogenesis and/or pre-clinical testing of antiviral drugs and vaccines. http://www.mdpi.com/1999-4915/4/1/62/ Mon, 09 Jan 2012 00:00:00 CET Viruses 2012-01-09 4 1 Review 62 82 1999-4915 Animal Models of Dengue Virus Infection 2012-01-09 doi: 10.3390/v4010062 Simona Zompi Eva Harris http://www.mdpi.com/1999-4915/4/1/28/ The sexually transmitted insect virus Helicoverpa zea nudivirus 2 (HzNV-2) was determined to have a circular double-stranded DNA genome of 231,621 bp coding for an estimated 113 open reading frames (ORFs). HzNV-2 is most closely related to the nudiviruses, a sister group of the insect baculoviruses. Several putative ORFs that share homology with the baculovirus core genes were identified in the viral genome. However, HzNV-2 lacks several key genetic features of baculoviruses including the late transcriptional regulation factor, LEF-1 and the palindromic hrs, which serve as origins of replication. The HzNV-2 genome was found to code for three ORFs that had significant sequence homology to cellular genes which are not generally found in viral genomes. These included a presumed juvenile hormone esterase gene, a gene coding for a putative zinc-dependent matrix metalloprotease, and a major facilitator superfamily protein gene; all of which are believed to play a role in the cellular proliferation and the tissue hypertrophy observed in the malformation of reproductive organs observed in HzNV-2 infected corn earworm moths, Helicoverpa zea. http://www.mdpi.com/1999-4915/4/1/28/ Fri, 06 Jan 2012 00:00:00 CET Viruses 2012-01-06 4 1 Article 28 61 1999-4915 Analysis of the Genome of the Sexually Transmitted Insect Virus Helicoverpa zea Nudivirus 2 2012-01-06 doi: 10.3390/v4010028 John P. Burand Woojin Kim Claudio L. Afonso Edan R. Tulman Gerald F. Kutish Zhiqiang Lu Daniel L. Rock http://www.mdpi.com/1999-4915/4/1/1/ Infection with Hepatitis C Virus (HCV) causes chronic disease in approximately 80% of cases, resulting in chronic inflammation and cirrhosis. Current treatments are not completely effective, and a vaccine has yet to be developed. Spontaneous resolution of infection is associated with effective host adaptive immunity to HCV, including production of both HCV-specific T cells and neutralizing antibodies. However, the supporting role of soluble innate factors in protection against HCV is less well understood. The innate immune system provides an immediate line of defense against infections, triggering inflammation and playing a critical role in activating adaptive immunity. Innate immunity comprises both cellular and humoral components, the humoral arm consisting of pattern recognition molecules such as complement C1q, collectins and ficolins. These molecules activate the complement cascade, neutralize pathogens, and recruit antigen presenting cells. Here we review the current understanding of anti-viral components of the humoral innate immune system that play a similar role to antibodies, describing their role in immunity to HCV and their potential contribution to HCV pathogenesis. http://www.mdpi.com/1999-4915/4/1/1/ Thu, 05 Jan 2012 00:00:00 CET Viruses 2012-01-05 4 1 Article 1 27 1999-4915 The Role of Humoral Innate Immunity in Hepatitis C Virus Infection 2012-01-05 doi: 10.3390/v4010001 Alexander W. Tarr Richard A. Urbanowicz Jonathan K. Ball http://www.mdpi.com/1999-4915/3/12/2462/ Many diverse viruses target a polarized epithelial monolayer during host invasion. The polarized epithelium is adept at restricting the movement of solutes, ions, macromolecules, and pathogens across the mucosa. This regulation can be attributed to the presence of a junctional complex between adjacent cells and to an intricate network of actin filaments that provides support to the subapical membrane and stabilizes intercellular junctions. It is therefore not surprising that many viruses have evolved highly varied strategies to dissolve or modulate the cortical actin meshwork to promote infection of polarized cells. In this review, we will discuss the cell biological properties of the actin cytoskeleton in polarized epithelial cells and review the known mechanisms utilized by viral pathogens to manipulate this system in order to facilitate their infection. http://www.mdpi.com/1999-4915/3/12/2462/ Wed, 21 Dec 2011 00:00:00 CET Viruses 2011-12-21 3 12 Review 2462 2477 1999-4915 The Actin Cytoskeleton as a Barrier to Virus Infection of Polarized Epithelial Cells 2011-12-21 doi: 10.3390/v3122462 Elizabeth Delorme-Axford Carolyn B. Coyne http://www.mdpi.com/1999-4915/3/12/2442/ The cell lines of the NCI-60 panel represent different cancer types and have been widely utilized for drug screening and molecular target identification. Screening these cell lines for envelope proteins or gene sequences related to xenotropic murine leukemia viruses (X-MLVs) revealed that one cell line, EKVX, was a candidate for production of an infectious gammaretrovirus. The presence of a retrovirus infectious to human cells was confirmed by the cell-free transmission of infection to the human prostate cancer cell line LNCaP. Amplification and sequencing of additional proviral sequences from EKVX confirmed a high degree of similarity to X-MLV. The cell line EKVX was established following passage of the original tumor cells through nude mice, providing a possible source of the X-MLV found in the EKVX cells. http://www.mdpi.com/1999-4915/3/12/2442/ Mon, 19 Dec 2011 00:00:00 CET Viruses 2011-12-19 3 12 Communication 2442 2461 1999-4915 The Human Lung Adenocarcinoma Cell Line EKVX Produces an Infectious Xenotropic Murine Leukemia Virus 2011-12-19 doi: 10.3390/v3122442 Joan L. Cmarik Jami A. Troxler Charlotte A. Hanson Xiang Zhang Sandra K. Ruscetti http://www.mdpi.com/1999-4915/3/12/2425/ The dynamics of viruses are critical to our understanding of disease pathogenesis. Using honey bee Deformed wing virus (DWV) as a model, we conducted field and laboratory studies to investigate the roles of abiotic and biotic stress factors as well as host health conditions in dynamics of virus replication in honey bees. The results showed that temperature decline could lead to not only significant decrease in the rate for pupae to emerge as adult bees, but also an increased severity of the virus infection in emerged bees, partly explaining the high levels of winter losses of managed honey bees, Apis mellifera, around the world. By experimentally exposing adult bees with variable levels of parasitic mite Varroa destructor, we showed that the severity of DWV infection was positively correlated with the density and time period of Varroa mite infestation, confirming the role of Varroa mites in virus transmission and activation in honey bees. Further, we showed that host conditions have a significant impact on the outcome of DWV infection as bees that originate from strong colonies resist DWV infection and replication significantly better than bee originating from weak colonies. The information obtained from this study has important implications for enhancing our understanding of host‑pathogen interactions and can be used to develop effective disease control strategies for honey bees. http://www.mdpi.com/1999-4915/3/12/2425/ Wed, 14 Dec 2011 00:00:00 CET Viruses 2011-12-14 3 12 Article 2425 2441 1999-4915 Dynamics of Persistent and Acute Deformed Wing Virus Infections in Honey Bees, Apis mellifera 2011-12-14 doi: 10.3390/v3122425 Gennaro Di Prisco Xuan Zhang Francesco Pennacchio Emilio Caprio Jilian Li Jay D. Evans Gloria DeGrandi-Hoffman Michele Hamilton Yan Ping Chen http://www.mdpi.com/1999-4915/3/12/2412/ Intrinsic antiviral resistance is a branch of antiviral defence that involves constitutively expressed cellular proteins that act within individual infected cells. In recent years it has been discovered that components of cellular nuclear structures known as ND10 or PML nuclear bodies contribute to intrinsic resistance against a variety of viruses, notably of the herpesvirus family. Several ND10 components are rapidly recruited to sites that are closely associated with herpes simplex virus type 1 (HSV-1) genomes during the earliest stages of infection, and this property correlates with the efficiency of ND10 mediated restriction of HSV-1 replication. Similar but distinct recruitment of certain DNA damage response proteins also occurs during infection. These recruitment events are inhibited in a normal wild type HSV-1 infection by the viral regulatory protein ICP0. HSV‑1 mutants that do not express ICP0 are highly susceptible to repression through intrinsic resistance factors, but they replicate more efficiently in cells depleted of certain ND10 proteins or in which ND10 component recruitment is inefficient. This article presents the background to this recruitment phenomenon and summaries how it is conveniently studied by fluorescence microscopy. http://www.mdpi.com/1999-4915/3/12/2412/ Wed, 07 Dec 2011 00:00:00 CET Viruses 2011-12-07 3 12 Review 2412 2424 1999-4915 The Use of Fluorescence Microscopy to Study the Association Between Herpesviruses and Intrinsic Resistance Factors 2011-12-07 doi: 10.3390/v3122412 Roger D. Everett http://www.mdpi.com/1999-4915/3/12/2396/ The virologic synapse (VS), which is formed between a virus-infected and uninfected cell, plays a central role in the transmission of certain viruses, such as HIV and HTLV-1. During VS formation, HTLV-1-infected T-cells polarize cellular and viral proteins toward the uninfected T-cell. This polarization resembles anterior-posterior cell polarity induced by immunological synapse (IS) formation, which is more extensively characterized than VS formation and occurs when a T-cell interacts with an antigen-presenting cell. One measure of cell polarity induced by both IS or VS formation is the repositioning of the microtubule organizing center (MTOC) relative to the contact point with the interacting cell. Here we describe an automated, high throughput system to score repositioning of the MTOC and thereby cell polarity establishment. The method rapidly and accurately calculates the angle between the MTOC and the IS for thousands of cells. We also show that the system can be adapted to score anterior-posterior polarity establishment of epithelial cells. This general approach represents a significant advancement over manual cell polarity scoring, which is subject to experimenter bias and requires more time and effort to evaluate large numbers of cells. http://www.mdpi.com/1999-4915/3/12/2396/ Mon, 28 Nov 2011 00:00:00 CET Viruses 2011-11-28 3 12 Article 2396 2411 1999-4915 High Throughput Method to Quantify Anterior-Posterior Polarity of T-Cells and Epithelial Cells 2011-11-28 doi: 10.3390/v3122396 Charletha V. Irvin-Wilson Justin Y. Newberg Kathleen Kong Ronald T. Javier Susan J. Marriott http://www.mdpi.com/1999-4915/3/12/2374/ Dengue viruses (DENV) are the causative agents of dengue fever (DF) and dengue hemorrhagic fever (DHF). Here we review the current state of knowledge about the human antibody response to dengue and identify important knowledge gaps. A large body of work has demonstrated that antibodies can neutralize or enhance DENV infection. Investigators have mainly used mouse monoclonal antibodies (MAbs) to study interactions between DENV and antibodies. These studies indicate that antibody neutralization of DENVs is a “multi-hit” phenomenon that requires the binding of multiple antibodies to neutralize a virion. The most potently neutralizing mouse MAbs bind to surface exposed epitopes on domain III of the dengue envelope (E) protein. One challenge facing the dengue field now is to extend these studies with mouse MAbs to better understand the human antibody response. The human antibody response is complex as it involves a polyclonal response to primary and secondary infections with 4 different DENV serotypes. Here we review studies conducted with immune sera and MAbs isolated from people exposed to dengue infections. Most dengue-specific antibodies in human immune sera are weakly neutralizing and bind to multiple DENV serotypes. The human antibodies that potently and type specifically neutralize DENV represent a small fraction of the total DENV-specific antibody response. Moreover, these neutralizing antibodies appear to bind to novel epitopes including complex, quaternary epitopes that are only preserved on the intact virion. These studies establish that human and mouse antibodies recognize distinct epitopes on the dengue virion. The leading theory proposed to explain the increased risk of severe disease in secondary cases is antibody dependent enhancement (ADE), which postulates that weakly neutralizing antibodies from the first infection bind to the second serotype and enhance infection of FcγR bearing myeloid cells such as monocytes and macrophages. Here we review results from human, animal and cell culture studies relevant to the ADE hypothesis. By understanding how human antibodies neutralize or enhance DENV, it will be possible to better evaluate existing vaccines and develop the next generation of novel vaccines. http://www.mdpi.com/1999-4915/3/12/2374/ Fri, 25 Nov 2011 00:00:00 CET Viruses 2011-11-25 3 12 Review 2374 2395 1999-4915 The Human Antibody Response to Dengue Virus Infection 2011-11-25 doi: 10.3390/v3122374 Wahala M. P. B. Wahala Aravinda M. de Silva http://www.mdpi.com/1999-4915/3/11/2351/ Ranaviruses are capable of infecting amphibians from at least 14 families and over 70 individual species. Ranaviruses infect multiple cell types, often culminating in organ necrosis and massive hemorrhaging. Subclinical infections have been documented, although their role in ranavirus persistence and emergence remains unclear. Water is an effective transmission medium for ranaviruses, and survival outside the host may be for significant duration. In aquatic communities, amphibians, reptiles and fish may serve as reservoirs. Controlled studies have shown that susceptibility to ranavirus infection and disease varies among amphibian species and developmental stages, and likely is impacted by host-pathogen coevolution, as well as, exogenous environmental factors. Field studies have demonstrated that the likelihood of epizootics is increased in areas of cattle grazing, where aquatic vegetation is sparse and water quality is poor. Translocation of infected amphibians through commercial trade (e.g., food, fish bait, pet industry) contributes to the spread of ranaviruses. Such introductions may be of particular concern, as several studies report that ranaviruses isolated from ranaculture, aquaculture, and bait facilities have greater virulence (i.e., ability to cause disease) than wild-type isolates. Future investigations should focus on the genetic basis for pathogen virulence and host susceptibility, ecological and anthropogenic mechanisms contributing to emergence, and vaccine development for use in captive populations and species reintroduction programs. http://www.mdpi.com/1999-4915/3/11/2351/ Tue, 22 Nov 2011 00:00:00 CET Viruses 2011-11-22 3 11 Review 2351 2373 1999-4915 Ecopathology of Ranaviruses Infecting Amphibians 2011-11-22 doi: 10.3390/v3112351 Debra Miller Matthew Gray Andrew Storfer http://www.mdpi.com/1999-4915/3/11/2339/ The enhanced viral susceptibility of the gypsy moth (Lymantria dispar)-derived IPLB-Ld652Y cell line has made it a popular in vitro system for studying virus-related phenomena in the Lepidoptera. Using both single-pass EST sequencing and 454-based pyrosequencing, a transcriptomic library of 14,368 putatively unique transcripts (PUTs) was produced comprising 8,476,050 high-quality, informative bases. The gene content of the IPLB-Ld652Y transcriptome was broadly assessed via comparison with the NCBI non‑redundant protein database, and more detailed functional annotation was inferred by comparison to the Swiss-Prot subset of UniProtKB. In addition to L. dispar cellular transcripts, a diverse array of both RNA and DNA virus-associated transcripts was identified within the dataset, suggestive of a high level of viral expression and activity in IPLB-Ld652Y cells. These sequence resources will provide a sound basis for developing testable experimental hypotheses by insect virologists, and suggest a number of avenues for potential research. http://www.mdpi.com/1999-4915/3/11/2339/ Mon, 21 Nov 2011 00:00:00 CET Viruses 2011-11-21 3 11 Article 2339 2350 1999-4915 The Lymantria dispar IPLB-Ld652Y Cell Line Transcriptome Comprises Diverse Virus-Associated Transcripts 2011-11-21 doi: 10.3390/v3112339 Michael E. Sparks Dawn E. Gundersen-Rindal http://www.mdpi.com/1999-4915/3/11/2328/ As intracellular parasites, viruses require a host cell in order to replicate. However, they face a series of cellular responses against infection. One of these responses is the activation of the double-stranded RNA (dsRNA)-activated protein kinase R (PKR). PKR phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), which in turn results in global protein synthesis inhibition and formation of stress granules (SGs). Recent studies have shown that SGs can interfere with the replicative cycle of certain viruses. This review addresses how viruses have evolved different control strategies at the SG level to ensure an efficient replication cycle during the cellular stress response triggered by the viral infection. http://www.mdpi.com/1999-4915/3/11/2328/ Fri, 18 Nov 2011 00:00:00 CET Viruses 2011-11-18 3 11 Review 2328 2338 1999-4915 Stress Granules in the Viral Replication Cycle 2011-11-18 doi: 10.3390/v3112328 Hilda Montero Vicenta Trujillo-Alonso http://www.mdpi.com/1999-4915/3/11/2301/ The complete genome of the Orgyia leucostigma nucleopolyhedrovirus (OrleNPV) isolated from the whitemarked tussock moth (Orgyia leucostigma, Lymantridae: Lepidoptera) was sequenced, analyzed, and compared to other baculovirus genomes. The size of the OrleNPV genome was 156,179 base pairs (bp) and had a G+C content of 39%. The genome encoded 135 putative open reading frames (ORFs), which occupied 79% of the entire genome sequence. Three inhibitor of apoptosis (ORFs 16, 43 and 63), and five baculovirus repeated ORFs (bro-a through bro-e) were interspersed in the OrleNPV genome. In addition to six direct repeat (drs), a common feature shared among most baculoviruses, OrleNPV genome contained three homologous regions (hrs) that are located in the latter half of the genome. The presence of an F-protein homologue and the results from phylogenetic analyses placed OrleNPV in the genus Alphabaculovirus, group II. Overall, OrleNPV appears to be most closely related to group II alphabaculoviruses Ectropis obliqua (EcobNPV), Apocheima cinerarium (ApciNPV), Euproctis pseudoconspersa (EupsNPV), and Clanis bilineata (ClbiNPV). http://www.mdpi.com/1999-4915/3/11/2301/ Tue, 15 Nov 2011 00:00:00 CET Viruses 2011-11-15 3 11 Article 2301 2327 1999-4915 Complete Sequence, Analysis and Organization of the Orgyia leucostigma Nucleopolyhedrovirus Genome 2011-11-15 doi: 10.3390/v3112301 David K. Thumbi Robert J. M. Eveleigh Christopher J. Lucarotti Renée Lapointe Robert I. Graham Lillian Pavlik Hilary A. M. Lauzon Basil M. Arif http://www.mdpi.com/1999-4915/3/11/2280/ Hepatitis C virus (HCV) represents a major public health problem, affecting 3% of the world’s population. The majority of infected individuals develop chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. To date, a vaccine is not available and current therapy is limited by resistance, adverse effects and high costs. Although it is very well established that cell-mediated immunity is necessary for viral clearance, the importance of host antibodies in clearing HCV infection is being increasingly recognized. Indeed, recent studies indicate that neutralizing antibodies are induced in the early phase of infection by patients who subsequently clear viral infection. Conversely, patients who do not clear the virus develop high titers of neutralizing antibodies during the chronic stage. Surprisingly, these antibodies are not able to control HCV infection. HCV has therefore developed mechanisms to evade immune elimination, allowing it to persist in the majority of infected individuals. A detailed understanding of the mechanisms by which the virus escapes immune surveillance is therefore necessary if novel preventive and therapeutic treatments have to be designed. This review summarizes the current knowledge of the mechanisms used by HCV to evade host neutralizing antibodies. http://www.mdpi.com/1999-4915/3/11/2280/ Tue, 15 Nov 2011 00:00:00 CET Viruses 2011-11-15 3 11 Review 2280 2300 1999-4915 Hepatitis C Virus Evasion Mechanisms from Neutralizing Antibodies 2011-11-15 doi: 10.3390/v3112280 Caterina Di Lorenzo Allan G. N. Angus Arvind H. Patel http://www.mdpi.com/1999-4915/3/11/2255/ Macrophages are important target cells for HIV-1 infection that play significant roles in the maintenance of viral reservoirs and other aspects of pathogenesis. Understanding the determinants of HIV-1 tropism for macrophages will inform HIV-1 control and eradication strategies. Tropism for macrophages is both qualitative (infection or not) and quantitative (replication capacity). For example many R5 HIV-1 isolates cannot infect macrophages, but for those that can the macrophage replication capacity can vary by up to 1000-fold. Some X4 viruses are also capable of replication in macrophages, indicating that cellular tropism is partially independent of co-receptor preference. Preliminary data obtained with a small number of transmitted/founder viruses indicate inefficient macrophage infection, whereas isolates from later in disease are more frequently tropic for macrophages. Thus tropism may evolve over time, and more macrophage tropic viruses may be implicated in the pathogenesis of advanced HIV-1 infection. Compartmentalization of macrophage-tropic brain-derived envelope glycoproteins (Envs), and non-macrophage tropic non-neural tissue-derived Envs points to adaptation of HIV-1 quasi-species in distinct tissue microenvironments. Mutations within and adjacent to the Env-CD4 binding site have been identified that determine macrophage tropism at the entry level, but post-entry molecular determinants of macrophage replication capacity involving HIV-1 accessory proteins need further definition. http://www.mdpi.com/1999-4915/3/11/2255/ Tue, 15 Nov 2011 00:00:00 CET Viruses 2011-11-15 3 11 Review 2255 2279 1999-4915 Viral Determinants of HIV-1 Macrophage Tropism 2011-11-15 doi: 10.3390/v3112255 Christopher J. A. Duncan Quentin J. Sattentau http://www.mdpi.com/1999-4915/3/11/2238/ Hepatitis C Virus (HCV) assembly process is the least understood step in the virus life cycle. The functional data revealed by forward and reverse genetics indicated that both structural and non-structural proteins are involved in the assembly process. Using confocal and electron microscopy different groups determined the subcellular localization of different viral proteins and they identified the lipid droplets (LDs) as the potential viral assembly site. Here, we aim to review the mechanisms that govern the viral proteins recruitment to LDs and discuss the current model of HCV assembly process. Based on previous examples, this review will also discuss advanced imaging techniques as potential means to extend our present knowledge of HCV assembly process. http://www.mdpi.com/1999-4915/3/11/2238/ Tue, 15 Nov 2011 00:00:00 CET Viruses 2011-11-15 3 11 Review 2238 2254 1999-4915 Hepatitis C Virus Assembly Imaging 2011-11-15 doi: 10.3390/v3112238 Costin-Ioan Popescu Yves Rouillé Jean Dubuisson http://www.mdpi.com/1999-4915/3/11/2223/ Foamy viruses (FVs) are distinct retroviruses classified as Spumaretrovirinae in contrast to the other retroviruses, the Orthoretrovirinae. As a unique feature of FVs, Gag is not sufficient for sub-viral particle (SVP) release. In primate and feline FVs (PFV and FFV), particle budding completely depends on the cognate FV Env glycoproteins. It was recently shown that an artificially added N-terminal Gag myristoylation signal (myr-signal) overcomes this restriction in PFV inducing an Orthoretrovirus-like budding phenotype. Here we show that engineered, heterologous N-terminal myr-signals also induce budding of the distantly related FFV Gag. The budding efficiency depends on the myr-signal and its location relative to the N-terminus of Gag. When the first nine amino acid residues of FFV Gag were replaced by known myr-signals, the budding efficiency as determined by the detection of extracellular SVPs was low. In contrast, adding myr-signals to the intact N‑terminus of FFV Gag resulted in a more efficient SVP release. Importantly, budding of myr-Gag proteins was sensitive towards inhibition of cellular N-myristoyltransferases. As expected, the addition or insertion of myr-signals that allowed Env-independent budding of FFV SVPs also retargeted Gag to plasma membrane-proximal sites and other intracellular membrane compartments. The data confirm that membrane-targeted FV Gag has the capacity of SVP formation. http://www.mdpi.com/1999-4915/3/11/2223/ Mon, 14 Nov 2011 00:00:00 CET Viruses 2011-11-14 3 11 Article 2223 2237 1999-4915 N-Terminally Myristoylated Feline Foamy Virus Gag Allows Env-Independent Budding of Sub-Viral Particles 2011-11-14 doi: 10.3390/v3112223 Yang Liu Yong-Boum Kim Martin Löchelt http://www.mdpi.com/1999-4915/3/11/2214/ Hymenoptera is a very large and ancient insect order encompassing bees, wasps, ants and sawflies. Fossil records indicate that they existed over 200 million years ago and about 100 million years before the appearance of Lepidoptera. Sawflies have been major pests in many parts of the world and some have caused serious forest defoliation in North America. All baculoviruses isolated from sawflies are of the single nucleocapsids phenotype and appear to replicate in midgut cells only. This group of viruses has been shown to be excellent pest control agents and three have been registered in Canada and Britain for this purpose. Sawfly baculoviruses contain the smallest genome of all baculoviruses sequenced so far. Gene orders among sequenced sawfly baculoviruses are co-linear but this is not shared with the genomes of lepidopteran baculoviruses. One distinguishing feature among all sequenced sawfly viruses is the lack of a gene encoding a membrane fusion protein, which brought into question the role of the budded virus phenotype in Gammabaculovirus biology. http://www.mdpi.com/1999-4915/3/11/2214/ Thu, 10 Nov 2011 00:00:00 CET Viruses 2011-11-10 3 11 Review 2214 2222 1999-4915 Biology and Genomics of Viruses Within the Genus Gammabaculovirus 2011-11-10 doi: 10.3390/v3112214 Basil Arif Shannon Escasa Lillian Pavlik http://www.mdpi.com/1999-4915/3/11/2192/ Feline immunodeficiency virus (FIV) is widespread in feline populations and causes an AIDS-like illness in domestic cats. It is highly prevalent in several endangered feline species. In domestic cats FIV infection is a valuable small animal model for HIV infection. In recent years there has been a significant increase in interest in FIV, in part to exploit this, but also because of the potential it has as a human gene therapy vector. Though much less studied than HIV there are many parallels in the replication of the two viruses, but also important differences and, despite their likely common origin, the viruses have in some cases used alternative strategies to overcome similar problems. Recent advances in understanding the structure and function of FIV RNA and proteins and their interactions has enhanced our knowledge of FIV replication significantly, however, there are still many gaps. This review summarizes our current knowledge of FIV molecular biology and its similarities with, and differences from, other lentiviruses. http://www.mdpi.com/1999-4915/3/11/2192/ Wed, 09 Nov 2011 00:00:00 CET Viruses 2011-11-09 3 11 Review 2192 2213 1999-4915 The Molecular Biology of Feline Immunodeficiency Virus (FIV) 2011-11-09 doi: 10.3390/v3112192 Julia C. Kenyon Andrew M. L. Lever http://www.mdpi.com/1999-4915/3/11/2160/ Herpesviruses are host specific pathogens that are widespread among vertebrates. Genome sequence data demonstrate that most herpesviruses of fish and amphibians are grouped together (family Alloherpesviridae) and are distantly related to herpesviruses of reptiles, birds and mammals (family Herpesviridae). Yet, many of the biological processes of members of the order Herpesvirales are similar. Among the conserved characteristics are the virion structure, replication process, the ability to establish long term latency and the manipulation of the host immune response. Many of the similar processes may be due to convergent evolution. This overview of identified herpesviruses of fish discusses the diseases that alloherpesviruses cause, the biology of these viruses and the host-pathogen interactions. Much of our knowledge on the biology of Alloherpesvirdae is derived from research with two species: Ictalurid herpesvirus 1 (channel catfish virus) and Cyprinid herpesvirus 3 (koi herpesvirus). http://www.mdpi.com/1999-4915/3/11/2160/ Tue, 08 Nov 2011 00:00:00 CET Viruses 2011-11-08 3 11 Review 2160 2191 1999-4915 Herpesviruses that Infect Fish 2011-11-08 doi: 10.3390/v3112160 Larry Hanson Arnon Dishon Moshe Kotler http://www.mdpi.com/1999-4915/3/11/2146/ Human endogenous retroviruses (HERVs) represent approximately 8% of our genome. HERVs influence cellular gene expression and contribute to normal physiological processes such as cellular differentiation and morphogenesis. HERVs have also been associated with certain pathological conditions, including cancer and neurodegenerative diseases. As HTLV-1 causes adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has been shown to modulate host gene expression mainly through the expression of the powerful Tax transactivator, herein we were interested in looking at the potential modulation capacity of HTLV-1 Tax on HERV expression. In order to evaluate the promoter activity of different HERV LTRs, pHERV-LTR-luc constructs were co-transfected in Jurkat T-cells with a Tax expression vector. Tax expression potently increased the LTR activity of HERV-W8 and HERV-H (MC16). In parallel, Jurkat cells were also stimulated with different T-cell-activating agents and HERV LTRs were observed to respond to different combination of Forskolin, bpV[pic] a protein tyrosine phosphatase inhibitor, and PMA. Transfection of expression vectors for different Tax mutants in Jurkat cells showed that several transcription factors including CREB appeared to be important for HERV-W8 LTR activation. Deletion mutants were derived from the HERV-W8 LTR and the region from −137 to −123 was found to be important for LTR response following Tax expression in Jurkat cells, while a different region was shown to be required in cells treated with activators. Our results thus demonstrated that HTLV-1 Tax activates several HERV LTRs. This raises the possibility that upregulated HERV expression could be involved in diseases associated with HTLV-1 infection. http://www.mdpi.com/1999-4915/3/11/2146/ Wed, 02 Nov 2011 00:00:00 CET Viruses 2011-11-02 3 11 Article 2146 2159 1999-4915 Activation of LTRs from Different Human Endogenous Retrovirus (HERV) Families by the HTLV-1 Tax Protein and T-Cell Activators 2011-11-02 doi: 10.3390/v3112146 Chirine Toufaily Sebastien Landry Christine Leib-Mosch Eric Rassart Benoit Barbeau http://www.mdpi.com/1999-4915/3/11/2127/ A critical first step in a “rational vaccine design” approach for hepatitis C virus (HCV) is to identify the most relevant mechanisms of immune protection. Emerging evidence provides support for a protective role of virus neutralizing antibodies, and the ability of the B cell response to modify the course of acute HCV infection. This has been made possible by the development of in vitro cell culture models, based on HCV retroviral pseudotype particles expressing E1E2 and infectious cell culture-derived HCV virions, and small animal models that are robust tools in studies of antibody-mediated virus neutralization. This review is focused on the immunogenic determinants on the E2 glycoprotein mediating virus neutralization and the pathways in which the virus is able to escape from immune containment. Encouraging findings from recent studies provide support for the existence of broadly neutralization antibodies that are not associated with virus escape. The identification of conserved epitopes mediating virus neutralization that are not associated with virus escape will facilitate the design of a vaccine immunogen capable of eliciting broadly neutralizing antibodies against this highly diverse virus. http://www.mdpi.com/1999-4915/3/11/2127/ Wed, 02 Nov 2011 00:00:00 CET Viruses 2011-11-02 3 11 Review 2127 2145 1999-4915 Neutralizing Antibody Response to Hepatitis C Virus 2011-11-02 doi: 10.3390/v3112127 Yong Wang Zhen-Yong Keck Steven K. H. Foung http://www.mdpi.com/1999-4915/3/11/2087/ A large number of viruses have been described in many different reptiles. These viruses include arboviruses that primarily infect mammals or birds as well as viruses that are specific for reptiles. Interest in arboviruses infecting reptiles has mainly focused on the role reptiles may play in the epidemiology of these viruses, especially over winter. Interest in reptile specific viruses has concentrated on both their importance for reptile medicine as well as virus taxonomy and evolution. The impact of many viral infections on reptile health is not known. Koch’s postulates have only been fulfilled for a limited number of reptilian viruses. As diagnostic testing becomes more sensitive, multiple infections with various viruses and other infectious agents are also being detected. In most cases the interactions between these different agents are not known. This review provides an update on viruses described in reptiles, the animal species in which they have been detected, and what is known about their taxonomic positions. http://www.mdpi.com/1999-4915/3/11/2087/ Tue, 01 Nov 2011 00:00:00 CET Viruses 2011-11-01 3 11 Review 2087 2126 1999-4915 Viruses Infecting Reptiles 2011-11-01 doi: 10.3390/v3112087 Rachel E. Marschang http://www.mdpi.com/1999-4915/3/11/2065/ Although a variety of virus species can infect amphibians, diseases caused by ranaviruses ([RVs]; Iridoviridae) have become prominent, and are a major concern for biodiversity, agriculture and international trade. The relatively recent and rapid increase in prevalence of RV infections, the wide range of host species infected by RVs, the variability in host resistance among population of the same species and among different developmental stages, all suggest an important involvement of the amphibian immune system. Nevertheless, the roles of the immune system in the etiology of viral diseases in amphibians are still poorly investigated. We review here the current knowledge of antiviral immunity in amphibians, focusing on model species such as the frog Xenopus and the salamander (Ambystoma tigrinum), and on recent progress in generating tools to better understand how host immune defenses control RV infections, pathogenicity, and transmission. http://www.mdpi.com/1999-4915/3/11/2065/ Mon, 31 Oct 2011 00:00:00 CET Viruses 2011-10-31 3 11 Review 2065 2086 1999-4915 Antiviral Immunity in Amphibians 2011-10-31 doi: 10.3390/v3112065 Guangchun Chen Jacques Robert http://www.mdpi.com/1999-4915/3/11/2047/ Using RNA-seq digital difference expression profiling methods, we have assessed the gene expression profiles of hemocytes harvested from Heliothis virescens that were challenged with Helicoverpa zea single nucleopolyhedrovirus (HzSNPV). A reference transcriptome of hemocyte-expressed transcripts was assembled from 202 million 42-base tags by combining the sequence data of all samples, and the assembled sequences were then subject to BLASTx analysis to determine gene identities. We used the fully sequenced HzSNPV reference genome to align 477,264 Illumina sequence tags from infected hemocytes in order to document expression of HzSNPV genes at early points during infection. A comparison of expression profiles of control insects to those lethally infected with HzSNPV revealed differential expression of key cellular stress response genes and genes involved in lipid metabolism. Transcriptional regulation of specific insect hormones in baculovirus-infected insects was also altered. A number of transcripts bearing homology to retroviral elements that were detected add to a growing body of evidence for extensive invasion of errantiviruses into the insect genome. Using this method, we completed the first and most comprehensive gene expression survey of both baculoviral infection and host immune defense in lepidopteran larvae. http://www.mdpi.com/1999-4915/3/11/2047/ Fri, 28 Oct 2011 00:00:00 CEST Viruses 2011-10-28 3 11 Article 2047 2064 1999-4915 Baculovirus Induced Transcripts in Hemocytes from the Larvae of Heliothis virescens 2011-10-28 doi: 10.3390/v3112047 Jonathan E. Breitenbach Kent S. Shelby Holly J.R. Popham http://www.mdpi.com/1999-4915/3/11/2025/ The growing global demand for seafood together with the limited capacity of the wild-capture sector to meet this demand has seen the aquaculture industry continue to grow around the world. A vast array of aquatic animal species is farmed in high density in freshwater, brackish and marine systems where they are exposed to new environments and potentially new diseases. On-farm stresses may compromise their ability to combat infection, and farming practices facilitate rapid transmission of disease. Viral pathogens, whether they have been established for decades or whether they are newly emerging as disease threats, are particularly challenging since there are few, if any, efficacious treatments, and the development of effective viral vaccines for delivery in aquatic systems remains elusive. Here, we review a few of the more significant viral pathogens of finfish, including aquabirnaviruses and infectious hematopoietic necrosis virus which have been known since the first half of the 20th century, and more recent viral pathogens, for example betanodaviruses, that have emerged as aquaculture has undergone a dramatic expansion in the past few decades. http://www.mdpi.com/1999-4915/3/11/2025/ Tue, 25 Oct 2011 00:00:00 CEST Viruses 2011-10-25 3 11 Review 2025 2046 1999-4915 Viruses of Fish: An Overview of Significant Pathogens 2011-10-25 doi: 10.3390/v3112025 Mark Crane Alex Hyatt http://www.mdpi.com/1999-4915/3/10/2006/ Hepatitis C virus (HCV) is a Flavivirus with a positive-sense, single-stranded RNA genome of about 9,600 nucleotides. It is a major cause of liver disease, infecting almost 200 million people all over the world. Similarly to most RNA viruses, HCV displays very high levels of genetic diversity which have been used to differentiate six major genotypes and about 80 subtypes. Although the different genotypes and subtypes share basic biological and pathogenic features they differ in clinical outcomes, response to treatment and epidemiology. The first HCV recombinant strain, in which different genome segments derived from parentals of different genotypes, was described in St. Petersburg (Russia) in 2002. Since then, there have been only a few more than a dozen reports including descriptions of HCV recombinants at all levels: between genotypes, between subtypes of the same genotype and even between strains of the same subtype. Here, we review the literature considering the reasons underlying the difficulties for unequivocally establishing recombination in this virus along with the analytical methods necessary to do it. Finally, we analyze the potential consequences, especially in clinical practice, of HCV recombination in light of the coming new therapeutic approaches against this virus. http://www.mdpi.com/1999-4915/3/10/2006/ Mon, 24 Oct 2011 00:00:00 CEST Viruses 2011-10-24 3 10 Review 2006 2024 1999-4915 Recombination in Hepatitis C Virus 2011-10-24 doi: 10.3390/v3102006 Fernando González-Candelas F. Xavier López-Labrador María Alma Bracho http://www.mdpi.com/1999-4915/3/10/1986/ Lentiviruses are known for their narrow cell- and species-tropisms, which are determined by cellular proteins whose absence or presence either support viral replication (dependency factors, cofactors) or inhibit viral replication (restriction factors). Similar to Human immunodeficiency virus type 1 (HIV-1), the cat lentivirus Feline immunodeficiency virus (FIV) is sensitive to recently discovered cellular restriction factors from non-host species that are able to stop viruses from replicating. Of particular importance are the cellular proteins APOBEC3, TRIM5α and tetherin/BST-2. In general, lentiviruses counteract or escape their species’ own variant of the restriction factor, but are targeted by the orthologous proteins of distantly related species. Most of the knowledge regarding lentiviral restriction factors has been obtained in the HIV-1 system; however, much less is known about their effects on other lentiviruses. We describe here the molecular mechanisms that explain how FIV maintains its replication in feline cells, but is largely prevented from cross-species infections by cellular restriction factors. http://www.mdpi.com/1999-4915/3/10/1986/ Fri, 21 Oct 2011 00:00:00 CEST Viruses 2011-10-21 3 10 Review 1986 2005 1999-4915 Cellular Restriction Factors of Feline Immunodeficiency Virus 2011-10-21 doi: 10.3390/v3101986 Jörg Zielonka Carsten Münk http://www.mdpi.com/1999-4915/3/10/1959/ Frog virus 3 (FV3) is the best characterized member of the family Iridoviridae. FV3 study has provided insights into the replication of other family members, and has served as a model of viral transcription, genome replication, and virus-mediated host-shutoff. Although the broad outlines of FV3 replication have been elucidated, the precise roles of most viral proteins remain unknown. Current studies using knock down (KD) mediated by antisense morpholino oligonucleotides (asMO) and small, interfering RNAs (siRNA), knock out (KO) following replacement of the targeted gene with a selectable marker by homologous recombination, ectopic viral gene expression, and recombinant viral proteins have enabled researchers to systematically ascertain replicative- and virulence-related gene functions. In addition, the application of molecular tools to ecological studies is providing novel ways for field biologists to identify potential pathogens, quantify infections, and trace the evolution of ecologically important viral species. In this review, we summarize current studies using not only FV3, but also other iridoviruses infecting ectotherms. As described below, general principles ascertained using FV3 served as a model for the family, and studies utilizing other ranaviruses and megalocytiviruses have confirmed and extended our understanding of iridovirus replication. Collectively, these and future efforts will elucidate molecular events in viral replication, intrinsic and extrinsic factors that contribute to disease outbreaks, and the role of the host immune system in protection from disease. http://www.mdpi.com/1999-4915/3/10/1959/ Thu, 20 Oct 2011 00:00:00 CEST Viruses 2011-10-20 3 10 Review 1959 1985 1999-4915 The Molecular Biology of Frog Virus 3 and other Iridoviruses Infecting Cold-Blooded Vertebrates 2011-10-20 doi: 10.3390/v3101959 V. Gregory Chinchar Kwang H. Yu James K. Jancovich http://www.mdpi.com/1999-4915/3/10/1933/ All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the ‘Big Bang’ theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features. http://www.mdpi.com/1999-4915/3/10/1933/ Thu, 20 Oct 2011 00:00:00 CEST Viruses 2011-10-20 3 10 Review 1933 1958 1999-4915 Viral Ancestors of Antiviral Systems 2011-10-20 doi: 10.3390/v3101933 Luis P. Villarreal http://www.mdpi.com/1999-4915/3/10/1909/ Despite the induction of effective immune responses, 80% of hepatitis C virus (HCV)-infected individuals progress from acute to chronic hepatitis. In contrast to the cellular immune response, the role of the humoral immune response in HCV clearance is still subject to debate. Indeed, HCV escapes neutralizing antibodies in chronically infected patients and reinfection has been described in human and chimpanzee. Studies of antibody-mediated HCV neutralization have long been hampered by the lack of cell-culture-derived virus and the absence of a small animal model. However, the development of surrogate models and recent progress in HCV propagation in vitro now enable robust neutralization assays to be performed. These advances are beginning to shed some light on the mechanisms of HCV neutralization. This review summarizes the current state of knowledge of the viral targets of anti-HCV-neutralizing antibodies and the mechanisms that enable HCV to evade the humoral immune response. The recent description of the HCV glycan shield that reduces the immunogenicity of envelope proteins and masks conserved neutralizing epitopes at their surface constitutes the major focus of this review. http://www.mdpi.com/1999-4915/3/10/1909/ Fri, 14 Oct 2011 00:00:00 CEST Viruses 2011-10-14 3 10 Review 1909 1932 1999-4915 The Hepatitis C Virus Glycan Shield and Evasion of the Humoral Immune Response 2011-10-14 doi: 10.3390/v3101909 François Helle Gilles Duverlie Jean Dubuisson http://www.mdpi.com/1999-4915/3/10/1891/ We developed a feline model of lentiviral cross-species transmission using a puma lentivirus (PLV or FIVPco) which infects domestic cats but does not cause disease. Infection with PLV protects cats from CD4+ T-cell decline caused by subsequent infection with virulent feline immunodeficiency virus (FIV). Previous studies implicate innate immune and/or cellular restriction mechanisms for FIV disease attenuation in PLV-infected cats. In this study, we evaluated viral infection and cytokine mRNA transcription in 12 different tissue reservoirs approximately five months post infection. We quantitated tissue proviral load, viral mRNA load and relative transcription of IL-10, IL-12p40 and IFNγ from tissues of cats exposed to FIV, PLV or both viruses and analyzed these parameters using a multivariate statistical approach. The distribution and intensity of FIV infection and IFNγ transcription differed between single and co-infected cats, characterized by higher FIV proviral loads and IFNγ expression in co-infected cat tissues. Variability in FIV mRNA load and IFNγ was significantly more constrained in co-infected versus singly infected cat tissues. Single-infected:co-infected ratios of FIV mRNA load compared to FIV proviral load indicated that active viral transcription was apparently inhibited during co-infection. These results indicate that previous PLV infection increases activation of tissue innate immunity and constrains the ability of FIV to productively infect tissue reservoirs of infection for months, independent of FIV proviral load, supporting a model in which innate immunity and/or modulation of target cell susceptibility play a key role in PLV-induced protection from FIV disease. http://www.mdpi.com/1999-4915/3/10/1891/ Thu, 13 Oct 2011 00:00:00 CEST Viruses 2011-10-13 3 10 Article 1891 1908 1999-4915 Prior Virus Exposure Alters the Long-Term Landscape of Viral Replication during Feline Lentiviral Infection 2011-10-13 doi: 10.3390/v3101891 Xin Zheng Scott Carver Ryan M. Troyer Julie A. Terwee Sue VandeWoude http://www.mdpi.com/1999-4915/3/10/1870/ One of the major obstacles that must be overcome in the design of effective lentiviral vaccines is the ability of lentiviruses to evolve in order to escape from neutralizing antibodies. The primary target for neutralizing antibodies is the highly variable viral envelope glycoprotein (Env), a glycoprotein that is essential for viral entry and comprises both variable and conserved regions. As a result of the complex trimeric nature of Env, there is steric hindrance of conserved epitopes required for receptor binding so that these are not accessible to antibodies. Instead, the humoral response is targeted towards decoy immunodominant epitopes on variable domains such as the third hypervariable loop (V3) of Env. For feline immunodeficiency virus (FIV), as well as the related human immunodeficiency virus-1 (HIV-1), little is known about the factors that lead to the development of broadly neutralizing antibodies. In cats infected with FIV and patients infected with HIV-1, only rarely are plasma samples found that contain antibodies capable of neutralizing isolates from other clades. In this review we examine the neutralizing response to FIV, comparing and contrasting with the response to HIV. We ask whether broadly neutralizing antibodies are induced by FIV infection and discuss the comparative value of studies of neutralizing antibodies in FIV infection for the development of more effective vaccine strategies against lentiviral infections in general, including HIV-1. http://www.mdpi.com/1999-4915/3/10/1870/ Thu, 13 Oct 2011 00:00:00 CEST Viruses 2011-10-13 3 10 Review 1870 1890 1999-4915 Feline Immunodeficiency Virus (FIV) Neutralization: A Review 2011-10-13 doi: 10.3390/v3101870 Margaret J. Hosie Daniela Pajek Ayman Samman Brian J. Willett http://www.mdpi.com/1999-4915/3/10/1849/ Insects are commonly infected with multiple viruses including those that cause sublethal, asymptomatic, and latent infections. Traditional methods for virus isolation typically lack the sensitivity required for detection of such viruses that are present at low abundance. In this respect, next generation sequencing technologies have revolutionized methods for the discovery and identification of new viruses from insects. Here we review both traditional and modern methods for virus discovery, and outline analysis of transcriptome and small RNA data for identification of viral sequences. We will introduce methods for de novo assembly of viral sequences, identification of potential viral sequences from BLAST data, and bioinformatics for generating full-length or near full-length viral genome sequences. We will also discuss implications of the ubiquity of viruses in insects and in insect cell lines. All of the methods described in this article can also apply to the discovery of viruses in other organisms. http://www.mdpi.com/1999-4915/3/10/1849/ Mon, 10 Oct 2011 00:00:00 CEST Viruses 2011-10-10 3 10 Review 1849 1869 1999-4915 Next Generation Sequencing Technologies for Insect Virus Discovery 2011-10-10 doi: 10.3390/v3101849 Sijun Liu Diveena Vijayendran Bryony C. Bonning http://www.mdpi.com/1999-4915/3/10/1836/ Although no physical fossils of viruses have been found, retroviruses are known to leave their molecular fossils in the genomes of their hosts, the so-called endogenous retroviral elements. These have provided us with important information about retroviruses in the past and their co-evolution with their hosts. On the other hand, because non‑retroviral viruses were considered not to leave such fossils, even the existence of prehistoric non-retroviral viruses has been enigmatic. Recently, we discovered that elements derived from ancient bornaviruses, non-segmented, negative strand RNA viruses, are found in the genomes of several mammalian species, including humans. In addition, at approximately the same time, several endogenous elements of RNA viruses, DNA viruses and reverse-transcribing DNA viruses have been independently reported, which revealed that non-retroviral viruses have played significant roles in the evolution of their hosts and provided novel insights into virology and cell biology. Here we review non-retroviral virus-like elements in vertebrate genomes, non-retroviral integration and the knowledge obtained from these endogenous non-retroviral virus-like elements. http://www.mdpi.com/1999-4915/3/10/1836/ Mon, 10 Oct 2011 00:00:00 CEST Viruses 2011-10-10 3 10 Review 1836 1848 1999-4915 Non-Retroviral Fossils in Vertebrate Genomes 2011-10-10 doi: 10.3390/v3101836 Masayuki Horie Keizo Tomonaga http://www.mdpi.com/1999-4915/3/10/1815/ Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and highly chemoresistant malignancy. Rho family GTPases regulate multiple signaling pathways in tumorigenesis: cytoskeletal organization, transcription, cell cycle progression, and cell proliferation. Geranylgeranylation of Rho family GTPases is essential for cell membrane localization and activation of these proteins. It is currently unknown whether HTLV-1-transformed cells are preferentially sensitive to geranylgeranylation inhibitors, such as GGTI-298. In this report, we demonstrate that GGTI-298 decreased cell viability and induced G2/M phase accumulation of HTLV-1-transformed cells, independent of p53 reactivation. HTLV-1-LTR transcriptional activity was inhibited and Tax protein levels decreased following treatment with GGTI-298. Furthermore, GGTI-298 decreased activation of NF-κB, a downstream target of Rho family GTPases. These studies suggest that protein geranylgeranylation contributes to dysregulation of cell survival pathways in HTLV-1-transformed cells. http://www.mdpi.com/1999-4915/3/10/1815/ Mon, 10 Oct 2011 00:00:00 CEST Viruses 2011-10-10 3 10 Article 1815 1835 1999-4915 Inhibition of Geranylgeranyl Transferase-I Decreases Cell Viability of HTLV-1-Transformed Cells 2011-10-10 doi: 10.3390/v3101815 Dustin C. Edwards Katherine M. McKinnon Claudio Fenizia Kyung-Jin Jung John N. Brady Cynthia A. Pise-Masison http://www.mdpi.com/1999-4915/3/10/1800/ Dengue has become the most important arboviral infection worldwide with more than 30 million cases of dengue fever estimated to occur each year. The need for a dengue vaccine is great and several live attenuated dengue candidate vaccines are proceeding through clinical evaluation. The need to induce a balanced immune response against all four DENV serotypes with a single vaccine has been a challenge for dengue vaccine developers. A live attenuated DENV chimeric vaccine produced by Sanofi Pasteur has recently entered Phase III evaluation in numerous dengue-endemic regions of the world. Viral interference between serotypes contained in live vaccines has required up to three doses of the vaccine be given over a 12-month period of time. For this reason, novel DENV candidate vaccines are being developed with the goal of achieving a protective immune response with an immunization schedule that can be given over the course of a few months. These next-generation candidates include DNA vaccines, recombinant adenovirus vectored vaccines, alphavirus replicons, and sub-unit protein vaccines. Several of these novel candidates will be discussed. http://www.mdpi.com/1999-4915/3/10/1800/ Mon, 26 Sep 2011 00:00:00 CEST Viruses 2011-09-26 3 10 Review 1800 1814 1999-4915 Next-Generation Dengue Vaccines: Novel Strategies Currently Under Development 2011-09-26 doi: 10.3390/v3101800 Anna P. Durbin Stephen S. Whitehead http://www.mdpi.com/1999-4915/3/9/1777/ Recombination in the family Coronaviridae has been well documented and is thought to be a contributing factor in the emergence and evolution of different coronaviral genotypes as well as different species of coronavirus. However, there are limited data available on the frequency and extent of recombination in coronaviruses in nature and particularly for the avian gamma-coronaviruses where only recently the emergence of a turkey coronavirus has been attributed solely to recombination. In this study, the full-length genomes of eight avian gamma-coronavirus infectious bronchitis virus (IBV) isolates were sequenced and along with other full-length IBV genomes available from GenBank were analyzed for recombination. Evidence of recombination was found in every sequence analyzed and was distributed throughout the entire genome. Areas that have the highest occurrence of recombination are located in regions of the genome that code for nonstructural proteins 2, 3 and 16, and the structural spike glycoprotein. The extent of the recombination observed, suggests that this may be one of the principal mechanisms for generating genetic and antigenic diversity within IBV. These data indicate that reticulate evolutionary change due to recombination in IBV, likely plays a major role in the origin and adaptation of the virus leading to new genetic types and strains of the virus. http://www.mdpi.com/1999-4915/3/9/1777/ Fri, 23 Sep 2011 00:00:00 CEST Viruses 2011-09-23 3 9 Article 1777 1799 1999-4915 Recombination in Avian Gamma-Coronavirus Infectious Bronchitis Virus 2011-09-23 doi: 10.3390/v3091777 Sharmi W. Thor Deborah A. Hilt Jessica C. Kissinger Andrew H. Paterson Mark W. Jackwood http://www.mdpi.com/1999-4915/3/9/1757/ Human immunodeficiency virus 1 (HIV-1) infects T cells, macrophages and dendritic cells and can manipulate their cytoskeleton structures at multiple steps during its replication cycle. Based on pharmacological and genetic targeting of cytoskeleton modulators, new imaging approaches and primary cell culture models, important roles for actin and microtubules during entry and cell-to-cell transfer have been established. Virological synapses and actin-containing membrane extensions can mediate HIV-1 transfer from dendritic cells or macrophage cells to T cells and between T cells. We will review the role of the cytoskeleton in HIV-1 entry, cellular trafficking and cell-to-cell transfer between primary cells. http://www.mdpi.com/1999-4915/3/9/1757/ Thu, 15 Sep 2011 00:00:00 CEST Viruses 2011-09-15 3 9 Review 1757 1776 1999-4915 How HIV-1 Takes Advantage of the Cytoskeleton during Replication and Cell-to-Cell Transmission 2011-09-15 doi: 10.3390/v3091757 Martin Lehmann Damjan S. Nikolic Vincent Piguet http://www.mdpi.com/1999-4915/3/9/1739/ Dengue virus (DENV) genome amplification is a process that involves the viral RNA, cellular and viral proteins, and a complex architecture of cellular membranes. The viral RNA is not a passive template during this process; it plays an active role providing RNA signals that act as promoters, enhancers and/or silencers of the replication process. RNA elements that modulate RNA replication were found at the 5' and 3' UTRs and within the viral coding sequence. The promoter for DENV RNA synthesis is a large stem loop structure located at the 5' end of the genome. This structure specifically interacts with the viral polymerase NS5 and promotes RNA synthesis at the 3' end of a circularized genome. The circular conformation of the viral genome is mediated by long range RNA-RNA interactions that span thousands of nucleotides. Recent studies have provided new information about the requirement of alternative, mutually exclusive, structures in the viral RNA, highlighting the idea that the viral genome is flexible and exists in different conformations. In this article, we describe elements in the promoter SLA and other RNA signals involved in NS5 polymerase binding and activity, and provide new ideas of how dynamic secondary and tertiary structures of the viral RNA participate in the viral life cycle. http://www.mdpi.com/1999-4915/3/9/1739/ Thu, 15 Sep 2011 00:00:00 CEST Viruses 2011-09-15 3 9 Review 1739 1756 1999-4915 Functional RNA Elements in the Dengue Virus Genome 2011-09-15 doi: 10.3390/v3091739 Leopoldo G. Gebhard Claudia V. Filomatori Andrea V. Gamarnik http://www.mdpi.com/1999-4915/3/9/1699/ Although single stranded (ss) DNA viruses that infect humans and their domesticated animals do not generally cause major diseases, the arthropod borne ssDNA viruses of plants do, and as a result seriously constrain food production in most temperate regions of the world. Besides the well known plant and animal-infecting ssDNA viruses, it has recently become apparent through metagenomic surveys of ssDNA molecules that there also exist large numbers of other diverse ssDNA viruses within almost all terrestrial and aquatic environments. The host ranges of these viruses probably span the tree of life and they are likely to be important components of global ecosystems. Various lines of evidence suggest that a pivotal evolutionary process during the generation of this global ssDNA virus diversity has probably been genetic recombination. High rates of homologous recombination, non-homologous recombination and genome component reassortment are known to occur within and between various different ssDNA virus species and we look here at the various roles that these different types of recombination may play, both in the day-to-day biology, and in the longer term evolution, of these viruses. We specifically focus on the ecological, biochemical and selective factors underlying patterns of genetic exchange detectable amongst the ssDNA viruses and discuss how these should all be considered when assessing the adaptive value of recombination during ssDNA virus evolution. http://www.mdpi.com/1999-4915/3/9/1699/ Tue, 13 Sep 2011 00:00:00 CEST Viruses 2011-09-13 3 9 Review 1699 1738 1999-4915 Recombination in Eukaryotic Single Stranded DNA Viruses 2011-09-13 doi: 10.3390/v3091699 Darren P. Martin Philippe Biagini Pierre Lefeuvre Michael Golden Philippe Roumagnac Arvind Varsani http://www.mdpi.com/1999-4915/3/9/1681/ Detailed analysis has been performed over many years of a geographic and temporal cohort of cats naturally infected with feline leukemia virus (FeLV). Molecular analysis of FeLV present in the diseased tissues and application of those viruses to experimental systems has revealed unique isolates with distinctive disease potential, previously uncharacterized virus-receptor interactions, information about the role of recombinant viruses in disease induction, and novel viral and cellular oncogenes implicated in pathogenesis, among other findings. The studies have contributed to an understanding of the selective forces that lead to predominance of distinctive FeLV isolates and disease outcomes in a natural population. http://www.mdpi.com/1999-4915/3/9/1681/ Fri, 09 Sep 2011 00:00:00 CEST Viruses 2011-09-09 3 9 Review 1681 1698 1999-4915 Viral Determinants of FeLV Infection and Pathogenesis: Lessons Learned from Analysis of a Natural Cohort 2011-09-09 doi: 10.3390/v3091681 Lisa L. Bolin Laura S. Levy http://www.mdpi.com/1999-4915/3/9/1650/ With constantly changing environmental selection pressures, retroviruses rely upon recombination to reassort polymorphisms in their genomes and increase genetic diversity, which improves the chances for the survival of their population. Recombination occurs during DNA synthesis, whereby reverse transcriptase undergoes template switching events between the two copackaged RNAs, resulting in a viral recombinant with portions of the genetic information from each parental RNA. This review summarizes our current understanding of the factors and mechanisms influencing retroviral recombination, fidelity of the recombination process, and evaluates the subsequent viral diversity and fitness of the progeny recombinant. Specifically, the high mutation rates and high recombination frequencies of HIV-1 will be analyzed for their roles in influencing HIV-1 global diversity, as well as HIV-1 diagnosis, drug treatment, and vaccine development. http://www.mdpi.com/1999-4915/3/9/1650/ Fri, 09 Sep 2011 00:00:00 CEST Viruses 2011-09-09 3 9 Review 1650 1680 1999-4915 Mechanisms and Factors that Influence High Frequency Retroviral Recombination 2011-09-09 doi: 10.3390/v3091650 Krista Delviks-Frankenberry Andrea Galli Olga Nikolaitchik Helene Mens Vinay K. Pathak Wei-Shau Hu http://www.mdpi.com/1999-4915/3/9/1634/ The Filoviridae family of viruses, which includes the genera Ebolavirus (EBOV) and Marburgvirus (MARV), causes severe and often times lethal hemorrhagic fever in humans. Filoviral infections are associated with ineffective innate antiviral responses as a result of virally encoded immune antagonists, which render the host incapable of mounting effective innate or adaptive immune responses. The Type I interferon (IFN) response is critical for establishing an antiviral state in the host cell and subsequent activation of the adaptive immune responses. Several filoviral encoded components target Type I IFN responses, and this innate immune suppression is important for viral replication and pathogenesis. For example, EBOV VP35 inhibits the phosphorylation of IRF-3/7 by the TBK-1/IKKε kinases in addition to sequestering viral RNA from detection by RIG-I like receptors. MARV VP40 inhibits STAT1/2 phosphorylation by inhibiting the JAK family kinases. EBOV VP24 inhibits nuclear translocation of activated STAT1 by karyopherin-α. The examples also represent distinct mechanisms utilized by filoviral proteins in order to counter immune responses, which results in limited IFN-α/β production and downstream signaling. http://www.mdpi.com/1999-4915/3/9/1634/ Wed, 07 Sep 2011 00:00:00 CEST Viruses 2011-09-07 3 9 Review 1634 1649 1999-4915 Filoviral Immune Evasion Mechanisms 2011-09-07 doi: 10.3390/v3091634 Parameshwaran Ramanan Reed S. Shabman Craig S. Brown Gaya K. Amarasinghe Christopher F. Basler Daisy W. Leung http://www.mdpi.com/1999-4915/3/9/1624/ The lentiviral accessory protein, Vpx, is known to counteract a restriction factor that is specific to myeloid cells, such as macrophages and dendritic cells. This review summarizes the findings in two seminal studies that identify SAMHD1 as the cellular protein that is responsible for myeloid cell restriction, and establish the existence of other types of restriction in these cells. http://www.mdpi.com/1999-4915/3/9/1624/ Mon, 05 Sep 2011 00:00:00 CEST Viruses 2011-09-05 3 9 Commentary 1624 1633 1999-4915 Restricted Access to Myeloid Cells Explained 2011-09-05 doi: 10.3390/v3091624 Vicente Planelles http://www.mdpi.com/1999-4915/3/9/1610/ Pathogens of bacterial and viral origin hijack pathways operating in eukaryotic cells in many ways in order to gain access into the host, to establish themselves and to eventually produce their progeny. The detailed molecular characterization of the subversion mechanisms devised by pathogens to infect host cells is crucial to generate targets for therapeutic intervention. Here we review recent data indicating that coronaviruses probably co-opt membranous carriers derived from the endoplasmic reticulum, which contain proteins that regulate disposal of misfolded polypeptides, for their replication. In addition, we also present models describing potential mechanisms that coronaviruses could employ for this hijacking. http://www.mdpi.com/1999-4915/3/9/1610/ Mon, 05 Sep 2011 00:00:00 CEST Viruses 2011-09-05 3 9 Review 1610 1623 1999-4915 Unconventional Use of LC3 by Coronaviruses through the Alleged Subversion of the ERAD Tuning Pathway 2011-09-05 doi: 10.3390/v3091610 Fulvio Reggiori Cornelis A.M. De Haan Maurizio Molinari http://www.mdpi.com/1999-4915/3/9/1609/ Although viruses infecting and affecting humans are the focus of considerable research effort, viruses that target other animal species, including cold-blooded vertebrates, are receiving increased attention. In part this reflects the interests of comparative virologists, but increasingly it is based on the impact that many viruses have on ecologically and commercially important animals. Frogs and other amphibians are sentinels of environmental health and their disappearance following viral or fungal (chytrid) infection is a cause for alarm. Likewise, because aquaculture and mariculture are providing an increasingly large percentage of the “seafood” consumed by humans, viral agents that adversely impact the harvest of cultured fish and amphibians are of equal concern. [...] http://www.mdpi.com/1999-4915/3/9/1609/ Fri, 02 Sep 2011 00:00:00 CEST Viruses 2011-09-02 3 9 Editorial 1609 1609 1999-4915 Special Issue: Viruses Infecting Fish, Amphibians, and Reptiles 2011-09-02 doi: 10.3390/v3091609 V. Gregory Chinchar http://www.mdpi.com/1999-4915/3/9/1562/ Dengue viruses (DENV) are by far the most important arboviral pathogens in the tropics around the world, putting at risk of infection nearly a third of the global human population. DENV are members of the genus Flavivirus in the Family Flaviviridae and comprise four antigenically distinct serotypes (DENV-1-4). Although they share almost identical epidemiological features, they are genetically distinct. Phylogenetic analyses have revealed valuable insights into the origins, epidemiology and the forces that shape DENV evolution in nature. In this review, we examine the current status of DENV evolution, including but not limited to rates of evolution, selection pressures, population sizes and evolutionary constraints, and we discuss how these factors influence transmission, pathogenesis and emergence. http://www.mdpi.com/1999-4915/3/9/1562/ Thu, 01 Sep 2011 00:00:00 CEST Viruses 2011-09-01 3 9 Review 1562 1608 1999-4915 Dengue — Quo tu et quo vadis? 2011-09-01 doi: 10.3390/v3091562 Rubing Chen Nikos Vasilakis http://www.mdpi.com/1999-4915/3/9/1549/ While autophagy has been shown to act as an anti-viral defense, the Picornaviridae avoid and, in many cases, subvert this pathway to promote their own replication. Evidence indicates that some picornaviruses hijack autophagy in order to induce autophagosome-like membrane structures for genomic RNA replication. Expression of picornavirus proteins can specifically induce the machinery of autophagy, although the mechanisms by which the viruses employ autophagy appear to differ. Many picornaviruses up-regulate autophagy in order to promote viral replication while some members of the family also inhibit degradation by autolysosomes. Here we explore the unusual relationship of this medically important family of viruses with a degradative mechanism of innate immunity. http://www.mdpi.com/1999-4915/3/9/1549/ Fri, 26 Aug 2011 00:00:00 CEST Viruses 2011-08-26 3 9 Review 1549 1561 1999-4915 Picornavirus Subversion of the Autophagy Pathway 2011-08-26 doi: 10.3390/v3091549 Kathryn A. Klein William T. Jackson http://www.mdpi.com/1999-4915/3/9/1532/ Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4+ T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4+ T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4+CD25+CCR4+ T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4+CD25+CCR4+ T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ+ T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease. http://www.mdpi.com/1999-4915/3/9/1532/ Thu, 25 Aug 2011 00:00:00 CEST Viruses 2011-08-25 3 9 Review 1532 1548 1999-4915 Human T-Lymphotropic Virus Type 1 (HTLV-1) and Regulatory T Cells in HTLV-1-Associated Neuroinflammatory Disease 2011-08-25 doi: 10.3390/v3091532 Natsumi Araya Tomoo Sato Naoko Yagishita Hitoshi Ando Atae Utsunomiya Steven Jacobson Yoshihisa Yamano http://www.mdpi.com/1999-4915/3/8/1501/ Marburg and Ebola viruses cause a severe hemorrhagic disease in humans with high fatality rates. Early target cells of filoviruses are monocytes, macrophages, and dendritic cells. The infection spreads to the liver, spleen and later other organs by blood and lymph flow. A hallmark of filovirus infection is the depletion of non-infected lymphocytes; however, the molecular mechanisms leading to the observed bystander lymphocyte apoptosis are poorly understood. Also, there is limited knowledge about the fate of infected cells in filovirus disease. In this review we will explore what is known about the intracellular events leading to virus amplification and cell damage in filovirus infection. Furthermore, we will discuss how cellular dysfunction and cell death may correlate with disease pathogenesis. http://www.mdpi.com/1999-4915/3/8/1501/ Wed, 24 Aug 2011 00:00:00 CEST Viruses 2011-08-24 3 8 Review 1501 1531 1999-4915 Intracellular Events and Cell Fate in Filovirus Infection 2011-08-24 doi: 10.3390/v3081501 Judith Olejnik Elena Ryabchikova Ronald B. Corley Elke Mühlberger http://www.mdpi.com/1999-4915/3/8/1485/ Adult T-cell leukemia (ATL) is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1) infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization of T-cells and transformation of other cell types. These processes may be aided by the ability of the viral protein to directly deregulate expression of specific cellular genes through interactions with numerous transcriptional regulators. To identify gene promoters where Tax is localized, we isolated Tax-DNA complexes from an HTLV-1-infected T-cell line through a chromatin immunoprecipitation (ChIP) assay and used the DNA to probe a CpG island microarray. A site within the RNASET2 gene was found to be occupied by Tax. Real-time PCR analysis confirmed this result, and transient expression of Tax in uninfected cells led to the recruitment of the viral protein to the promoter. This event correlated with a decrease in the level of RNase T2 mRNA and protein, suggesting that Tax represses expression of this gene. Loss of RNase T2 expression occurs in certain hematological malignancies and other forms of cancer, and RNase T2 was recently reported to function as a tumor suppressor. Consequently, a reduction in the level of RNase T2 by Tax may play a role in ATL development. http://www.mdpi.com/1999-4915/3/8/1485/ Thu, 18 Aug 2011 00:00:00 CEST Viruses 2011-08-18 3 8 Article 1485 1500 1999-4915 Direct Inhibition of RNAse T2 Expression by the HTLV-1 Viral Protein Tax 2011-08-18 doi: 10.3390/v3081485 Nicholas Polakowski Hongjin Han Isabelle Lemasson http://www.mdpi.com/1999-4915/3/8/1460/ Genetic recombination in RNA viruses was discovered many years ago for poliovirus (PV), an enterovirus of the Picornaviridae family, and studied using PV or other picornaviruses as models. Recently, recombination was shown to be a general phenomenon between different types of enteroviruses of the same species. In particular, the interest for this mechanism of genetic plasticity was renewed with the emergence of pathogenic recombinant circulating vaccine-derived polioviruses (cVDPVs), which were implicated in poliomyelitis outbreaks in several regions of the world with insufficient vaccination coverage. Most of these cVDPVs had mosaic genomes constituted of mutated poliovaccine capsid sequences and part or all of the non-structural sequences from other human enteroviruses of species C (HEV-C), in particular coxsackie A viruses. A study in Madagascar showed that recombinant cVDPVs had been co-circulating in a small population of children with many different HEV-C types. This viral ecosystem showed a surprising and extensive biodiversity associated to several types and recombinant genotypes, indicating that intertypic genetic recombination was not only a mechanism of evolution for HEV-C, but an usual mode of genetic plasticity shaping viral diversity. Results suggested that recombination may be, in conjunction with mutations, implicated in the phenotypic diversity of enterovirus strains and in the emergence of new pathogenic strains. Nevertheless, little is known about the rules and mechanisms which govern genetic exchanges between HEV-C types, as well as about the importance of intertypic recombination in generating phenotypic variation. This review summarizes our current knowledge of the mechanisms of evolution of PV, in particular recombination events leading to the emergence of recombinant cVDPVs. http://www.mdpi.com/1999-4915/3/8/1460/ Wed, 17 Aug 2011 00:00:00 CEST Viruses 2011-08-17 3 8 Review 1460 1484 1999-4915 Recombination between Poliovirus and Coxsackie A Viruses of Species C: A Model of Viral Genetic Plasticity and Emergence 2011-08-17 doi: 10.3390/v3081460 Nicolas Combelas Barbara Holmblat Marie-Line Joffret Florence Colbère-Garapin Francis Delpeyroux http://www.mdpi.com/1999-4915/3/8/1439/ The phenotype of HTLV-1-transformed CD4+ T lymphocytes largely depends on defined viral effector molecules such as the viral oncoprotein Tax. In this review, we exemplify the expression pattern of characteristic lineage markers, costimulatory receptors and ligands of the tumor necrosis factor superfamily, cytokine receptors, and adhesion molecules on HTLV-1-transformed cells. These molecules may provide survival signals for the transformed cells. Expression of characteristic surface markers might therefore contribute to persistence of HTLV-1-transformed lymphocytes and to the development of HTLV-1-associated disease. http://www.mdpi.com/1999-4915/3/8/1439/ Tue, 16 Aug 2011 00:00:00 CEST Viruses 2011-08-16 3 8 Review 1439 1459 1999-4915 Cell Surface Markers in HTLV-1 Pathogenesis 2011-08-16 doi: 10.3390/v3081439 Andrea K. Kress Ralph Grassmann Bernhard Fleckenstein http://www.mdpi.com/1999-4915/3/8/1432/ Viruses have attracted the interest of researchers from multiple disciplines and have nucleated many productive and innovative collaborations. In part, this is because viruses so intimately associate with their hosts that decoupling host and virus biology is difficult, and virus-host interactions occur at multiple scales, from within cells to populations, each of which is intrinsically complex. As a consequence, ecologists, population biologists, evolutionary biologists, and researchers from quantitative fields, including mathematics, statistics, physics and computer science, make significant contributions to the field of virology. Our understanding of virus dynamics and evolution has substantially benefited from these multidisciplinary efforts. It is now common to see advanced phylogenetic reconstruction methods used to determine the origins of emergent viruses, to estimate the effect of natural selection on virus populations, and to assess virus population dynamics. Mathematical and statistical models that elucidate complex virus and host interactions in time and space at the molecular and population level are appearing more regularly in virology and biomedical journals. Massive quantities of data now available due to technological innovation in imaging, increased disease surveillance efforts, and novel approaches to determine social contact structure are changing approaches to study the dynamics and evolution of viral infections in heterogeneous environments. The next decade presents exciting new opportunities and challenges for the expanding field of researchers investigating dynamics of viral infections that will lead to innovation and new insight on virus interactions in both individual hosts and in populations. The compilation of articles in this Special Issue on “Virus Dynamics and Evolution” is comprised of reviews and primary research, summarized below, that provide new perspectives on virus interactions with host organisms through the integration of empirical and computational analyses of virus at molecular, cellular, and population levels. http://www.mdpi.com/1999-4915/3/8/1432/ Tue, 16 Aug 2011 00:00:00 CEST Viruses 2011-08-16 3 8 Editorial 1432 1438 1999-4915 Virus Dynamics and Evolution: Bridging Scales and Disciplines 2011-08-16 doi: 10.3390/v3081432 Mary Poss http://www.mdpi.com/1999-4915/3/8/1417/ Following receptor-mediated uptake into endocytic vesicles and escape from the endosome, adenovirus is transported by cytoplasmic dynein along microtubules to the perinuclear region of the cell. How motor proteins are recruited to viruses for their own use has begun to be investigated only recently. We review here the evidence for a role for dynein and other motor proteins in adenovirus infectivity. We also discuss the implications of recent studies on the mechanism of dynein recruitment to adenovirus for understanding the relationship between pathogenic and physiological cargo recruitment and for the evolutionary origins of dynein-mediated adenovirus transport. http://www.mdpi.com/1999-4915/3/8/1417/ Fri, 12 Aug 2011 00:00:00 CEST Viruses 2011-08-12 3 8 Review 1417 1431 1999-4915 Adenovirus Recruits Dynein by an Evolutionary Novel Mechanism Involving Direct Binding to pH-Primed Hexon 2011-08-12 doi: 10.3390/v3081417 Julian Scherer Richard B Vallee http://www.mdpi.com/1999-4915/3/8/1415/ The authors would like to make the following corrections to their published paper: There was an error in calculation of IC50 fold changes for the NAI-resistant viruses reported in Table 1 of the above-mentioned paper. The corrected values are marked in the updated Table 1 below. http://www.mdpi.com/1999-4915/3/8/1415/ Fri, 12 Aug 2011 00:00:00 CEST Viruses 2011-08-12 3 8 Correction 1415 1416 1999-4915 Correction: Okomo-Adhiambo, M. et al. Neuraminidase Inhibitor Susceptibility Testing in Human Influenza Viruses: A Laboratory Surveillance Perspective. Viruses 2010, 2, 2269-2289 2011-08-12 doi: 10.3390/v3081415 Margaret Okomo-Adhiambo Katrina Sleeman Kristina Ballenger Ha T. Nguyen Vasiliy P. Mishin Tiffany G. Sheu James Smagala Yan Li Alexander I. Klimov Larisa V. Gubareva http://www.mdpi.com/1999-4915/3/8/1395/ The discovery of human retroviruses in the early 1980s revealed the existence of viral-encoded non-structural genes that were not evident in previously described animal retroviruses. Based on the absence or presence of these additional genes retroviruses were classified as ‘simple’ and ‘complex’, respectively. Expression of most of these extra genes is achieved through the generation of alternatively spliced mRNAs. The present review summarizes the genetic organization and expression strategies of human complex retroviruses and highlights the converging mechanisms controlling their life cycles. http://www.mdpi.com/1999-4915/3/8/1395/ Thu, 11 Aug 2011 00:00:00 CEST Viruses 2011-08-11 3 8 Review 1395 1414 1999-4915 Converging Strategies in Expression of Human Complex Retroviruses 2011-08-11 doi: 10.3390/v3081395 Ilaria Cavallari Francesca Rende Donna M. D'Agostino Vincenzo Ciminale http://www.mdpi.com/1999-4915/3/8/1374/ Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. Second, it primes development of the adaptive response, which completes the elimination of the pathogen or of infected cells. In vivo, HTLV-1 infects T lymphocytes that participate in adaptive immunity but also monocytes and dendritic cells that are major players in innate immunity. Herein, we will review the interplay between HTLV-1 and innate immunity. Particular emphasis is put on HTLV-1-induced alteration of type-I interferon (IFN-I) function. In vitro, the viral Tax protein plays a significant role in the alteration of IFN synthesis and signaling. Despite this, IFN-I/AZT treatment of Adult T‑cell Leukemia/Lymphoma (ATLL) patients leads to complete remission. We will discuss a model in which exogenous IFN-I could act both on the microenvironment of the T-cells to protect them from infection, and also on infected cells when combined with other drugs that lead to Tax down-regulation/degradation. http://www.mdpi.com/1999-4915/3/8/1374/ Mon, 08 Aug 2011 00:00:00 CEST Viruses 2011-08-08 3 8 Review 1374 1394 1999-4915 HTLV-1 and Innate Immunity 2011-08-08 doi: 10.3390/v3081374 Chloé Journo Renaud Mahieux http://www.mdpi.com/1999-4915/3/8/1358/ Recombination is an important process that influences biological evolution at many different levels. More and more homologous recombination events have been reported among negative sense RNA viruses recently. While sporadic authentic examples indicate that homologous recombination does occur, recombination seems to be generally rare or even absent in most negative sense RNA viruses, and most of the homologous recombination events reported in the literature were likely generated artificially due to lab contamination or inappropriate bioinformatics methods. Homologous recombination in negative sense RNA viruses should be reported with caution in the future, and only after stringent quality control efforts. Moreover, co-infection experiments should be performed to confirm whether recombination can occur. http://www.mdpi.com/1999-4915/3/8/1358/ Thu, 04 Aug 2011 00:00:00 CEST Viruses 2011-08-04 3 8 Review 1358 1373 1999-4915 Homologous Recombination in Negative Sense RNA Viruses 2011-08-04 doi: 10.3390/v3081358 Guan-Zhu Han Michael Worobey http://www.mdpi.com/1999-4915/3/8/1342/ Autophagy is a cellular process that catabolizes cytoplasmic components and maintains energy homeostasis. As a stress response, the autophagy machinery interconnects a wide range of cellular pathways, enhancing the spread of certain pathogens while limiting others, and has become a highly active research area over the past several years. Independent laboratories have recently reported that autophagy vesicles accumulate in hepatitis C virus (HCV) infected cells and that autophagy proteins can function as proviral factors required for HCV replication. In this review, we summarize what is currently known about the interplay between autophagy and HCV and the possible mechanisms whereby autophagy proteins might favor HCV propagation. http://www.mdpi.com/1999-4915/3/8/1342/ Thu, 04 Aug 2011 00:00:00 CEST Viruses 2011-08-04 3 8 Review 1342 1357 1999-4915 Impact of the Autophagy Machinery on Hepatitis C Virus Infection 2011-08-04 doi: 10.3390/v3081342 Marlène Dreux Francis V. Chisari http://www.mdpi.com/1999-4915/3/8/1332/ Several independent groups have published that autophagy is required for optimal RNA replication of dengue virus (DENV). Initially, it was postulated that autophagosomes might play a structural role in replication complex formation. However, cryo-EM tomography of DENV replication complexes showed that DENV replicates on endoplasmic reticulum (ER) cisternae invaginations and not on classical autophagosomes. Recently, it was reported that autophagy plays an indirect role in DENV replication by modulating cellular lipid metabolism. DENV-induced autophagosomes deplete cellular triglycerides that are stored in lipid droplets, leading to increased β-oxidation and energy production. This is the first example of a virus triggering autophagy to modulate cellular physiology. In this review, we summarize these data and discuss new questions and implications for autophagy during DENV replication. http://www.mdpi.com/1999-4915/3/8/1332/ Thu, 04 Aug 2011 00:00:00 CEST Viruses 2011-08-04 3 8 Review 1332 1341 1999-4915 Dengue Virus and Autophagy 2011-08-04 doi: 10.3390/v3081332 Nicholas S. Heaton Glenn Randall http://www.mdpi.com/1999-4915/3/8/1320/ Human T-lymphotropic virus type I (HTLV-I) infects an estimated 15–20 million persons worldwide. A number of diseases have been associated with the virus including adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-I uveitis, and HTLV-I-associated infective dermatitis. Once it was shown that there is an increased risk for developing HAM/TSP associated with blood transfusion, screening for HTLV-1 among blood banks was implemented in Japan, United States, France, and the Netherlands. This process includes detection by an enzyme immunoassay (EIA) followed by a confirmatory Western blot (WB) in which recombinant proteins specific for HTLV-I Env glycoproteins are incorporated into WB strips. HTLV-I seropositive results are defined by the presence of antibodies against either gp46 or gp62/68 (both Env protein bands) and either p19, p24, or p53 (one of the gag bands). HTLV-II seropositivity is confirmed by the presence of rgp46-II. However, numerous cases have been documented in which serum samples are reactive by EIA, but an incomplete banding pattern is displayed by subsequent confirmatory WB. Although the significance of these HTLV-I/II seroindeterminates is unclear, it may suggest a much higher incidence of exposure to HTLV-I/II than previously estimated. http://www.mdpi.com/1999-4915/3/8/1320/ Tue, 02 Aug 2011 00:00:00 CEST Viruses 2011-08-02 3 8 Review 1320 1331 1999-4915 The Prevalence and Significance of HTLV-I/II Seroindeterminate Western Blot Patterns 2011-08-02 doi: 10.3390/v3081320 Anna Abrams Yoshimi Akahata Steven Jacobson http://www.mdpi.com/1999-4915/3/8/1312/ Retroviruses are well known pathogens of mammals, birds and fish. Their potential to induce cancer in chickens was already described almost 100 years ago and murine retroviruses have been a subject of study for 50 years. The first human retroviruses, HTLV and HIV, were discovered more than 30 years ago, surprising researchers and physicians by the profound differences in the diseases they cause. HTLV-1 is able to induce, after decades of infection, lymphomas/leukemia or neuroimmune disorders whereas untreated HIV infection leads almost inevitably to AIDS. The recently described XMRV (xenotropic murine leukemia virus-related virus) appeared to possess many of the features known for HTLV and was regarded by some to be the third human retrovirus. However, recent publications by Knox et al. [1] and Paprotka et al. [2] have shed new light on this gammaretrovirus. Knox and colleagues clearly demonstrate that XMRV is absent in patients belonging to a chronic fatigue syndrome cohort who had previously been reported to be XMRV-positive [3]. This supports the growing suspicion that laboratory contamination was responsible for the postulated link between XMRV and the disease. Furthermore, Paprotka et al’s identification of XMRV’s origin and the phylogenetic analysis of known XMRV sequences are further nails in the coffin to the notion that XMRV is a clinically relevant infectious human retrovirus. http://www.mdpi.com/1999-4915/3/8/1312/ Wed, 27 Jul 2011 00:00:00 CEST Viruses 2011-07-27 3 8 Commentary 1312 1319 1999-4915 Origin of XMRV and its Demise as a Human Pathogen Associated with Chronic Fatigue Syndrome 2011-07-27 doi: 10.3390/v3081312 Oliver Hohn Norbert Bannert http://www.mdpi.com/1999-4915/3/7/1281/ The etiology of the intestinal disease Crohn’s disease involves genetic factors as well as ill-defined environmental agents. Several genetic variants linked to this disease are associated with autophagy, a process that is critical for proper responses to viral infections. While a role for viruses in this disease remains speculative, accumulating evidence indicate that this possibility requires serious consideration. In this review, we will examine the three-way relationship between viruses, autophagy genes, and Crohn’s disease and discuss how host-pathogen interactions can mediate complex inflammatory disorders. http://www.mdpi.com/1999-4915/3/7/1281/ Thu, 21 Jul 2011 00:00:00 CEST Viruses 2011-07-21 3 7 Review 1281 1311 1999-4915 Viruses, Autophagy Genes, and Crohn’s Disease 2011-07-21 doi: 10.3390/v3071281 Vanessa M. Hubbard Ken Cadwell http://www.mdpi.com/1999-4915/3/7/1249/ I present a hypothesis that begins with the proposal that abiotic ancestors of phage RNA and DNA packaging systems (and cells) include mobile shells with an internal, molecule-transporting cavity. The foundations of this hypothesis include the conjecture that current nucleic acid packaging systems have imprints from abiotic ancestors. The abiotic shells (1) initially imbibe and later also bind and transport organic molecules, thereby providing a means for producing molecular interactions that are links in the chain of events that produces ancestors to the first molecules that are both information carrying and enzymatically active, and (2) are subsequently scaffolds on which proteins assemble to form ancestors common to both shells of viral capsids and cell membranes. Emergence of cells occurs via aggregation and merger of shells and internal contents. The hypothesis continues by using proposed imprints of abiotic and biotic ancestors to deduce an ancestral thermal ratchet-based DNA packaging motor that subsequently evolves to integrate a DNA packaging ATPase that provides a power stroke. http://www.mdpi.com/1999-4915/3/7/1249/ Wed, 20 Jul 2011 00:00:00 CEST Viruses 2011-07-20 3 7 Article 1249 1280 1999-4915 Proposed Ancestors of Phage Nucleic Acid Packaging Motors (and Cells) 2011-07-20 doi: 10.3390/v3071249 Philip Serwer http://www.mdpi.com/1999-4915/3/7/1210/ Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads. http://www.mdpi.com/1999-4915/3/7/1210/ Tue, 19 Jul 2011 00:00:00 CEST Viruses 2011-07-19 3 7 Review 1210 1248 1999-4915 Preventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV 2011-07-19 doi: 10.3390/v3071210 Sabrina M. Rodríguez Arnaud Florins Nicolas Gillet Alix De Brogniez María Teresa Sánchez-Alcaraz Mathieu Boxus Fanny Boulanger Gerónimo Gutiérrez Karina Trono Irene Alvarez Lucas Vagnoni Luc Willems http://www.mdpi.com/1999-4915/3/7/1204/ The retrovirus restriction factor TRIM5α blocks post-entry infection of retroviruses in a species-specific manner. As a cellular E3 ubiquitin ligase, TRIM5α binds to the retroviral capsid lattice in the cytoplasm of an infected cell and accelerates the uncoating process of retroviral capsid, thus providing a potent restriction to HIV-1 and other retrovirus infections. The precise mechanism by which this restriction is imposed remains under scrutiny, and evidence is lacking to link the E3 ubiquitin ligase activity of TRIM5α to its ability to restrict retrovirus infection. In a recent study, Pertel and colleagues have uncovered the link between the two, providing compelling evidence to suggest that following the interaction with the retroviral capsid, TRIM5 triggers an antiviral innate immune response by functioning as a pattern recognition receptor [1]. This unique function of TRIM5 is dependent on its association with the E2 ubiquitin-conjugating enzyme complex UBC13-UEV1A and subsequent activation of the TAK1 kinase complex and downstream genes involved in innate immune responses. These findings have defined a novel function for TRIM5 as a pattern recognition receptor in innate immune recognition and provided valuable mechanistic insight into its role as a retroviral restriction factor. Here we discuss the significance of these new findings in understanding TRIM5-mediated HIV restriction. http://www.mdpi.com/1999-4915/3/7/1204/ Fri, 15 Jul 2011 00:00:00 CEST Viruses 2011-07-15 3 7 Commentary 1204 1209 1999-4915 TRIM5 Acts as More Than a Retroviral Restriction Factor 2011-07-15 doi: 10.3390/v3071204 Suresh De Silva Li Wu http://www.mdpi.com/1999-4915/3/7/1179/ As an early response to infection, cells induce a profile of the early inflammatory proteins including antiviral cytokines and chemokines. Two families of transcriptional factors play a major role in the transcriptional activation of the early inflammatory genes: The well-characterized family of NFkB factors and the family of interferon regulatory factors (IRF). The IRFs play a critical role in the induction of type I interferon (IFN) and chemokine genes, as well as genes mediating antiviral, antibacterial, and inflammatory responses. Type I IFNs represent critical components of innate antiviral immunity. These proteins not only exert direct antiviral effects, but also induce maturation of dendritic cells (DC), and enhance functions of NK, T and B cells, and macrophages. This review will summarize the current knowledge of the mechanisms leading to the innate antiviral response with a focus on its role in the regulation of HIV-1 infection and pathogenicity. We would like this review to be both historical and a future perspective. http://www.mdpi.com/1999-4915/3/7/1179/ Thu, 14 Jul 2011 00:00:00 CEST Viruses 2011-07-14 3 7 Review 1179 1203 1999-4915 Innate Antiviral Response: Role in HIV-1 Infection 2011-07-14 doi: 10.3390/v3071179 Paula M. Pitha http://www.mdpi.com/1999-4915/3/7/1166/ Macroautophagy is a catabolic pathway in eukaryotic cells that has recently been shown to facilitate pathogen detection, pathogen restriction and pathogen-derived antigen presentation to CD4+ T cells. Due to these protective functions during immune responses, several pathogens, including RNA and DNA viruses, have developed strategies to inhibit autophagosome generation or maturation. Interestingly, most of the respective viral proteins exert these functions via binding to Beclin-1, an essential macroautophagy protein that constitutes part of the phosphatidylinositol-3 kinase complexes that mark membranes for autophagosome generation and facilitate autophagosome fusion with lyososomes. The viruses that inhibit macroautophagy by this pathway include herpesviruses, HIV and influenza A virus. Inhibition either before or after autophagosome formation seems to benefit their viral replication by different mechanisms, which are discussed here. http://www.mdpi.com/1999-4915/3/7/1166/ Tue, 12 Jul 2011 00:00:00 CEST Viruses 2011-07-12 3 7 Review 1166 1178 1999-4915 Beclin-1 Targeting for Viral Immune Escape 2011-07-12 doi: 10.3390/v3071166 Christian Münz http://www.mdpi.com/1999-4915/3/7/1131/ Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1. http://www.mdpi.com/1999-4915/3/7/1131/ Tue, 12 Jul 2011 00:00:00 CEST Viruses 2011-07-12 3 7 Review 1131 1165 1999-4915 Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread 2011-07-12 doi: 10.3390/v3071131 Michael D. Lairmore Rajaneesh Anupam Nadine Bowden Robyn Haines Rashade A. H. Haynes II Lee Ratner Patrick L. Green http://www.mdpi.com/1999-4915/3/7/1112/ Virus infections elicit an immediate innate response involving antiviral factors. The activities of some of these factors are, in turn, blocked by viral countermeasures. The ensuing battle between the host and the viruses is crucial for determining whether the virus establishes a foothold and/or induces adaptive immune responses. A comprehensive systems-level understanding of the repertoire of anti-viral effectors in the context of these immediate virus-host responses would provide significant advantages in devising novel strategies to interfere with the initial establishment of infections. Recent efforts to identify cellular factors in a comprehensive and unbiased manner, using genome-wide siRNA screens and other systems biology “omics” methodologies, have revealed several potential anti-viral effectors for viruses like Human immunodeficiency virus type 1 (HIV-1), Hepatitis C virus (HCV), West Nile virus (WNV), and influenza virus. This review describes the discovery of novel viral restriction factors and discusses how the integration of different methods in systems biology can be used to more comprehensively identify the intimate interactions of viruses and the cellular innate resistance. http://www.mdpi.com/1999-4915/3/7/1112/ Mon, 11 Jul 2011 00:00:00 CEST Viruses 2011-07-11 3 7 Review 1112 1130 1999-4915 Systems-Biology Approaches to Discover Anti-Viral Effectors of the Human Innate Immune Response 2011-07-11 doi: 10.3390/v3071112 Carsten Münk Andreas F.R. Sommer Renate König http://www.mdpi.com/1999-4915/3/7/1091/ Natural killer (NK) cells’ major role in the control of viruses is to eliminate established infected cells. The capacity of NK cells to kill virus-infected cells is dependent on the interactions between ligands on the infected cell and receptors on the NK cell surface. Because of the importance of ligand-receptor interactions in modulating the NK cell cytotoxic response, HIV has developed strategies to regulate various NK cell ligands making the infected cell surprisingly refractory to NK cell lysis. This is perplexing because the HIV-1 accessory protein Vpr induces expression of ligands for the NK cell activating receptor, NKG2D. In addition, the accessory protein Nef removes the inhibitory ligands HLA-A and -B. The reason for the ineffective killing by NK cells despite the strong potential to eliminate infected cells is due to HIV-1 Vpu’s ability to down modulate the co-activation ligand, NTB-A, from the cell surface. Down modulation of NTB-A prevents efficient NK cell degranulation. This review will focus on the mechanisms through which the HIV-1 accessory proteins modulate their respective ligands, and its implication for NK cell killing of HIV-infected cells. http://www.mdpi.com/1999-4915/3/7/1091/ Fri, 08 Jul 2011 00:00:00 CEST Viruses 2011-07-08 3 7 Review 1091 1111 1999-4915 The Natural Killer Cell Cytotoxic Function Is Modulated by HIV-1 Accessory Proteins 2011-07-08 doi: 10.3390/v3071091 Bharatwaj Sowrirajan Edward Barker http://www.mdpi.com/1999-4915/3/7/1074/ Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). The high percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. STLV-3 viruses belong to the third PTLV type and are equally divergent from both HTLV-1 and HTLV-2. They are endemic in several monkey species that live in West, Central and East Africa. In 2005, we, and others reported the discovery of the human homolog (HTLV-3) of STLV-3 in two asymptomatic inhabitants from South Cameroon whose sera exhibited HTLV indeterminate serologies. More recently, two other cases of HTLV-3 infection in persons living in Cameroon were reported suggesting that this virus is not extremely rare in the human population living in Central Africa. Together with STLV-3, these human viral strains belong to the PTLV-3 group. A fourth HTLV type (HTLV-4) was also discovered in the same geographical area. The overall PTLV-3 and PTLV-4 genomic organization is similar to that of HTLV-1 and HTLV-2 with the exception of their long terminal repeats (LTRs) that contain only two 21 bp repeats. As in HTLV-1, HTLV-3 Tax contains a PDZ binding motif while HTLV-4 does not. An antisense transcript was also described in HTLV-3 transfected cells. PTLV-3 molecular clones are now available and will allow scientists to study the viral cycle, the tropism and the possible pathogenicity in vivo. Current studies are also aimed at determining the prevalence, distribution, and modes of transmission of these viruses, as well as their possible association with human diseases. Here we will review the characteristics of these new simian and human retroviruses, whose discovery has opened new avenues of research in the retrovirology field. http://www.mdpi.com/1999-4915/3/7/1074/ Fri, 08 Jul 2011 00:00:00 CEST Viruses 2011-07-08 3 7 Review 1074 1090 1999-4915 HTLV-3/STLV-3 and HTLV-4 Viruses: Discovery, Epidemiology, Serology and Molecular Aspects 2011-07-08 doi: 10.3390/v3071074 Renaud Mahieux Antoine Gessain http://www.mdpi.com/1999-4915/3/7/1059/ We previously hypothesized that increased capillary permeability observed in both hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) may be caused by hantavirus-specific cytotoxic T cells attacking endothelial cells presenting viral antigens on their surface based on clinical observations and in vitro experiments. In HCPS, hantavirus-specific T cell responses positively correlated with disease severity. In HFRS, in one report, contrary to HCPS, T cell responses negatively correlated with disease severity, but in another report the number of regulatory T cells, which are thought to suppress T cell responses, negatively correlated with disease severity. In rat experiments, in which hantavirus causes persistent infection, depletion of regulatory T cells helped infected rats clear virus without inducing immunopathology. These seemingly contradictory findings may suggest delicate balance in T cell responses between protection and immunopathogenesis. Both too strong and too weak T cell responses may lead to severe disease. It is important to clarify the role of T cells in these diseases for better treatment (whether to suppress T cell functions) and protection (vaccine design) which may need to take into account viral factors and the influence of HLA on T cell responses. http://www.mdpi.com/1999-4915/3/7/1059/ Wed, 06 Jul 2011 00:00:00 CEST Viruses 2011-07-06 3 7 Review 1059 1073 1999-4915 T Cells and Pathogenesis of Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever with Renal Syndrome 2011-07-06 doi: 10.3390/v3071059 Masanori Terajima Francis A. Ennis http://www.mdpi.com/1999-4915/3/7/1041/ Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd2 [S(−)C2, N-dmpa]2 (μ-dppe)Cl2}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas. http://www.mdpi.com/1999-4915/3/7/1041/ Tue, 05 Jul 2011 00:00:00 CEST Viruses 2011-07-05 3 7 Article 1041 1058 1999-4915 C7a, a Biphosphinic Cyclopalladated Compound, Efficiently Controls the Development of a Patient-Derived Xenograft Model of Adult T Cell Leukemia/Lymphoma 2011-07-05 doi: 10.3390/v3071041 Ana B. Guimaraes-Correa Lindsey B. Crawford Carlos R. Figueiredo Karina P. Gimenes Lorena A. Pinto Maria Fernanda Rios Grassi Gerold Feuer Luiz R. Travassos Antonio C.F. Caires Elaine G. Rodrigues Susan J. Marriott http://www.mdpi.com/1999-4915/3/7/1015/ Intermediate filaments (IF) are essential to maintain cellular and nuclear integrity and shape, to manage organelle distribution and motility, to control the trafficking and pH of intracellular vesicles, to prevent stress-induced cell death, and to support the correct distribution of specific proteins. Because of this, IF are likely to be targeted by a variety of pathogens, and may act in favor or against infection progress. As many IF functions remain to be identified, however, little is currently known about these interactions. Herpesviruses can infect a wide variety of cell types, and are thus bound to encounter the different types of IF expressed in each tissue. The analysis of these interrelationships can yield precious insights into how IF proteins work, and into how viruses have evolved to exploit these functions. These interactions, either known or potential, will be the focus of this review. http://www.mdpi.com/1999-4915/3/7/1015/ Mon, 04 Jul 2011 00:00:00 CEST Viruses 2011-07-04 3 7 Communication 1015 1040 1999-4915 Herpesviruses and Intermediate Filaments: Close Encounters with the Third Type 2011-07-04 doi: 10.3390/v3071015 Laura Hertel http://www.mdpi.com/1999-4915/3/7/1001/ The NF-κB pathway is intimately linked to the survival of mammalian cells, and its activation by Tax has consequently been considered important for human T-cell leukemia/lymphoma virus type 1 (HTLV-1)-infected cell resistance to death. Very little emphasis has been given to other mechanisms, although Tax regulates the expression and activity of several cellular genes. The finding that CREB protein is activated in HTLV-1 infected cells underlines the possibility that other mechanisms of survival may be implicated in HTLV-1 infection. Indeed, CREB activation or overexpression plays a role in normal hematopoiesis, as well as in leukemia development, and CREB is considered as a survival factor in various cell systems. A better understanding of the different molecular mechanisms used by Tax to counteract cell death will also help in the development of new therapeutic strategies for HTLV-1 associated diseases. http://www.mdpi.com/1999-4915/3/7/1001/ Mon, 27 Jun 2011 00:00:00 CEST Viruses 2011-06-27 3 7 Review 1001 1014 1999-4915 Anti-Apoptotic Effect of Tax: An NF-κB Path or a CREB Way? 2011-06-27 doi: 10.3390/v3071001 Daniela Saggioro http://www.mdpi.com/1999-4915/3/7/982/ Filoviruses can cause severe, often fatal hemorrhagic fever in humans. Recent advances in vaccine and therapeutic drug development have provided encouraging data concerning treatment of these infections. However, relatively little is known about immune responses in fatal versus non-fatal filovirus infection. This review summarizes the published literature on correlates of immunity to filovirus infection, and highlights deficiencies in our knowledge on this topic. It is likely that there are several types of successful immune responses, depending on the type of filovirus, and the presence and timing of vaccination or drug treatment. http://www.mdpi.com/1999-4915/3/7/982/ Mon, 27 Jun 2011 00:00:00 CEST Viruses 2011-06-27 3 7 Review 982 1000 1999-4915 Correlates of Immunity to Filovirus Infection 2011-06-27 doi: 10.3390/v3070982 Steven B. Bradfute Sina Bavari http://www.mdpi.com/1999-4915/3/7/941/ Following infection of exposed peripheral tissues, neurotropic alphaherpesviruses invade nerve endings and deposit their DNA genomes into the nuclei of neurons resident in ganglia of the peripheral nervous system. The end result of these events is the establishment of a life-long latent infection. Neuroinvasion typically requires efficient viral transmission through a polarized epithelium followed by long-distance transport through the viscous axoplasm. These events are mediated by the recruitment of the cellular microtubule motor proteins to the intracellular viral particle and by alterations to the cytoskeletal architecture. The focus of this review is the interplay between neurotropic herpesviruses and the cytoskeleton. http://www.mdpi.com/1999-4915/3/7/941/ Mon, 27 Jun 2011 00:00:00 CEST Viruses 2011-06-27 3 7 Review 941 981 1999-4915 Alphaherpesviruses and the Cytoskeleton in Neuronal Infections 2011-06-27 doi: 10.3390/v3070941 Sofia V. Zaichick Kevin P. Bohannon Gregory A. Smith http://www.mdpi.com/1999-4915/3/6/920/ The innate immune response to viral pathogens is critical in order to mobilize protective immunity. Cells of the innate immune system detect viral infection largely through germline-encoded pattern recognition receptors (PRRs) present either on the cell surface or within distinct intracellular compartments. These include the Toll-like receptors (TLRs), the retinoic acid-inducble gene I-like receptors (RLRs), the nucleotide oligomerization domain-like receptors (NLRs, also called NACHT, LRR and PYD domain proteins) and cytosolic DNA sensors. While in certain cases viral proteins are the trigger of these receptors, the predominant viral activators are nucleic acids. The presence of viral sensing PRRs in multiple cellular compartments allows innate cells to recognize and quickly respond to a broad range of viruses, which replicate in different cellular compartments. Here, we review the role of PRRs and associated signaling pathways in detecting viral pathogens in order to evoke production of interferons and cytokines. By highlighting recent progress in these areas, we hope to convey a greater understanding of how viruses activate PRR signaling and how this interaction shapes the anti-viral immune response. http://www.mdpi.com/1999-4915/3/6/920/ Thu, 23 Jun 2011 00:00:00 CEST Viruses 2011-06-23 3 6 Review 920 940 1999-4915 Pattern Recognition Receptors and the Innate Immune Response to Viral Infection 2011-06-23 doi: 10.3390/v3060920 Mikayla R. Thompson John J. Kaminski Evelyn A. Kurt-Jones Katherine A. Fitzgerald http://www.mdpi.com/1999-4915/3/6/906/ The RNA helicase family of RIG-I-like receptors (RLRs) is a key component of host defense mechanisms responsible for detecting viruses and triggering innate immune signaling cascades to control viral replication and dissemination. As cytoplasm-based sensors, RLRs recognize foreign RNA in the cell and activate a cascade of antiviral responses including the induction of type I interferons, inflammasome activation, and expression of proinflammatory cytokines and chemokines. This review provides a brief overview of RLR function, ligand interactions, and downstream signaling events with an expanded discussion on the therapeutic potential of targeting RLRs for immune stimulation and treatment of virus infection. http://www.mdpi.com/1999-4915/3/6/906/ Thu, 23 Jun 2011 00:00:00 CEST Viruses 2011-06-23 3 6 Review 906 919 1999-4915 RIG-I Like Receptors in Antiviral Immunity and Therapeutic Applications 2011-06-23 doi: 10.3390/v3060906 Reneé C. Ireton Michael Gale Jr. http://www.mdpi.com/1999-4915/3/6/901/ Retroviruses integrate a reverse transcribed double stranded DNA copy of their viral genome into the chromosomal DNA of cells they infect. Occasionally, exogenous retroviruses infect germ cells and when this happens a profound shift in the virus host dynamic occurs. Retroviruses maintained as hereditable viral genetic material are referred to as endogenous retroviruses (ERVs). After millions of years of co-evolution with their hosts many human ERVs retain some degree of function and a few have even become symbionts. Thousands of copies of endogenous retrovirus long terminal repeats (LTRs) exist in the human genome. There are approximately 3000 to 4000 copies of the ERV-9 LTRs in the human genome and like other solo LTRs, ERV-9 LTRs can exhibit distinct promoter/enhancer activity in different cell lineages. It has been recently reported that a novel transcript of p63, a primordial member of the p53 family, is under the transcriptional control of an ERV-9 LTR [1]. The expression of different p63 transcript isoforms has been previously shown to have an important role in replenishing cutaneous epithelial stem cells and maintaining the fidelity of the female germ line [2]. In this recent report, a novel p63 transcript, designated GTAp63, is described as specifically expressed in healthy human testes and germ cell precursors of human testes but not in testicular cancer cells. The ability of ERV-9 regulatory regions to contribute to the maintenance of male germ line stability is yet another example of how ERVs have evolved to serve an important function in the physiology of their human hosts. http://www.mdpi.com/1999-4915/3/6/901/ Tue, 21 Jun 2011 00:00:00 CEST Viruses 2011-06-21 3 6 Commentary 901 905 1999-4915 Role of Human Endogenous Retroviral Long Terminal Repeats (LTRs) in Maintaining the Integrity of the Human Germ Line 2011-06-21 doi: 10.3390/v3060901 Meihong Liu Maribeth V. Eiden http://www.mdpi.com/1999-4915/3/6/886/ Of the millions of HTLV-1 infected carriers worldwide, 3–5% will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy. The virus carries the Tax oncogene which constitutively activates the NFκB pathway. This co-option of signaling through NFκB provides for the HTLV-1 infected cell an escape from cell cycle arrest and apoptosis, a steady source of growth factors, and a mechanism by which the virus can activate its own target cell. Therapies that target the NFκB pathway sensitize adult T-cell leukemia/lymphoma (ATLL) cells to apoptosis. A focus on translational interrogation of NFκB inhibitors in animal models and ATLL patients is needed to advance NFκB-targeted ATLL therapies to the bedside. http://www.mdpi.com/1999-4915/3/6/886/ Tue, 21 Jun 2011 00:00:00 CEST Viruses 2011-06-21 3 6 Review 886 900 1999-4915 Targeting HTLV-1 Activation of NFκB in Mouse Models and ATLL Patients 2011-06-21 doi: 10.3390/v3060886 Daniel A. Rauch Lee Ratner http://www.mdpi.com/1999-4915/3/6/861/ The 3' end of the human T-cell leukemia/lymphoma virus type-1 (HTLV-1) genome contains four overlapping open reading frames (ORF) that encode regulatory proteins. Here, we review current knowledge of HTLV-1 orf-I and orf-II protein products. Singly spliced mRNA from orf-I encodes p12, which can be proteolytically cleaved to generate p8, while differential splicing of mRNA from orf-II results in production of p13 and p30. These proteins have been demonstrated to modulate transcription, apoptosis, host cell activation and proliferation, virus infectivity and transmission, and host immune responses. Though these proteins are not essential for virus replication in vitro, p8, p12, p13, and p30 have an important role in the establishment and maintenance of HTLV-1 infection in vivo. http://www.mdpi.com/1999-4915/3/6/861/ Fri, 17 Jun 2011 00:00:00 CEST Viruses 2011-06-17 3 6 Review 861 885 1999-4915 Orf-I and Orf-II-Encoded Proteins in HTLV-1 Infection and Persistence 2011-06-17 doi: 10.3390/v3060861 Dustin Edwards Claudio Fenizia Heather Gold Maria Fernanda de Castro-Amarante Cody Buchmann Cynthia A. Pise-Masison Genoveffa Franchini http://www.mdpi.com/1999-4915/3/6/858/ Studies of oncogenic viruses have made seminal contributions to the molecular biology of cancer. Key discoveries include the identification of viral oncogenes and cellular proto-oncogenes, elucidation of signal transduction pathways, and identification of tumor suppressor genes. The origins of cancer virology began almost exactly one hundred years ago with the discovery of avian sarcoma and acute leukemia viruses—RNA-containing viruses of the retrovirus family. The study of animal cancer viruses accelerated beginning in the late 1960s and early 1970s, with the discovery of DNA viruses that could transform cells in culture, and the development of quantitative assays for transformation by DNA and RNA-containing tumor viruses. The discovery of reverse transcriptase in retroviruses in 1970 also greatly accelerated research on these viruses. Indeed RNA and DNA tumor viruses led the way in cancer molecular biology during this era before molecular cloning. It was possible to physically purify virus particles and generate specific hybridization probes for viral DNA and RNA at a time when it was not possible to analyze cellular genes in the same manner. [...] http://www.mdpi.com/1999-4915/3/6/858/ Wed, 15 Jun 2011 00:00:00 CEST Viruses 2011-06-15 3 6 Editorial 858 860 1999-4915 Cell Transformation by RNA Viruses: An Overview 2011-06-15 doi: 10.3390/v3060858 Hung Fan http://www.mdpi.com/1999-4915/3/6/829/ The HTLV-1 Tax protein both activates viral replication and is involved in HTLV-1-mediated transformation of T lymphocytes. The transforming properties of Tax include altering the expression of select cellular genes via activation of cellular pathways and perturbation of both cell cycle control mechanisms and apoptotic signals. The recent discovery that Tax undergoes a hierarchical sequence of posttranslational modifications that control its intracellular localization provides provocative insights into the mechanisms regulating Tax transcriptional and transforming activities. http://www.mdpi.com/1999-4915/3/6/829/ Wed, 15 Jun 2011 00:00:00 CEST Viruses 2011-06-15 3 6 Review 829 857 1999-4915 Move or Die: the Fate of the Tax Oncoprotein of HTLV-1 2011-06-15 doi: 10.3390/v3060829 Julie Lodewick Isabelle Lamsoul Françoise Bex http://www.mdpi.com/1999-4915/3/6/811/ West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that is maintained in an enzootic cycle between mosquitoes and birds, but can also infect and cause disease in horses and humans. WNV is endemic in parts of Africa, Europe, the Middle East, and Asia, and since 1999 has spread to North America, Mexico, South America, and the Caribbean. WNV infects the central nervous system (CNS) and can cause severe disease in a small minority of infected humans, mostly immunocompromised or the elderly. This review discusses some of the mechanisms by which the immune system can limit dissemination of WNV infection and elaborates on the mechanisms involved in pathogenesis. Reasons for susceptibility to WNV-associated neuroinvasive disease in less than 1% of cases remain unexplained, but one favored hypothesis is that the involvement of the CNS is associated with a weak immune response allowing robust WNV replication in the periphery and spread of the virus to the CNS. http://www.mdpi.com/1999-4915/3/6/811/ Wed, 15 Jun 2011 00:00:00 CEST Viruses 2011-06-15 3 6 Review 811 828 1999-4915 West Nile Virus: Immunity and Pathogenesis 2011-06-15 doi: 10.3390/v3060811 Stephanie M. Lim Penelope Koraka Albert D.M.E. Osterhaus Byron E.E. Martina http://www.mdpi.com/1999-4915/3/6/794/ The initial step in retroviral infection involves specific interactions between viral envelope proteins (Env) and specific receptors on the surface of target cells. For many years, little was known about the entry receptors for HTLV-1. During this time, however, functional domains of the HTLV-1 Env were identified by analyzing the effects of neutralizing antibodies and specific mutations in Env on HTLV-1 infectivity. More recent studies have revealed that HTLV-1 infectivity involves interactions with three different molecules: heparan sulfate proteoglycans (HSPG), the VEGF-165 receptor Neuropilin 1 (NRP-1) and glucose transporter type 1 (GLUT1). Here, we revisit previously published data on the functional domains of Env in regard to the recent knowledge acquired about this multi-receptor complex. We also discuss the similarities and differences between HTLV-1 and other deltaretroviruses in regards to receptor usage. http://www.mdpi.com/1999-4915/3/6/794/ Wed, 15 Jun 2011 00:00:00 CEST Viruses 2011-06-15 3 6 Review 794 810 1999-4915 Molecular Aspects of HTLV-1 Entry: Functional Domains of the HTLV-1 Surface Subunit (SU) and Their Relationships to the Entry Receptors 2011-06-15 doi: 10.3390/v3060794 Kathryn S. Jones Sophie Lambert Manuella Bouttier Laurence Bénit Frank W. Ruscetti Olivier Hermine Claudine Pique