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Viruses, Volume 4, Issue 10 (October 2012), Pages 1844-2416

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Editorial

Jump to: Research, Review, Other

Open AccessEditorial An Interagency Collaboration to Facilitate Development of Filovirus Medical Countermeasures
Viruses 2012, 4(10), 2312-2316; doi:10.3390/v4102312
Received: 14 October 2012 / Revised: 16 October 2012 / Accepted: 17 October 2012 / Published: 19 October 2012
Cited by 7 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text
Abstract
The Filovirus Animal Non-Clinical Group (FANG) is a US interdepartmental and interagency group established to support and facilitate the advanced development of filovirus Medical Countermeasures (MCM), both vaccines and therapeutics. It is co-led by one representative from the Department of Defense (DoD), the
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The Filovirus Animal Non-Clinical Group (FANG) is a US interdepartmental and interagency group established to support and facilitate the advanced development of filovirus Medical Countermeasures (MCM), both vaccines and therapeutics. It is co-led by one representative from the Department of Defense (DoD), the first author, and one from the Department of Health and Human Services (HHS), the second author. The FANG membership includes operational level program staff and Subject Matter Experts (SME) from performing organizations as well as scientific staff and program managers from DoD and HHS funding and regulatory agencies. Focus areas include animal models, assays, reagents, product manufacture and characterization, and other interagency product development issues that will support Food and Drug Administration (FDA) licensure of safe and effective filovirus MCMs. The FANG continues to develop strategies to address broadly applicable and interagency product development challenges relevant to filovirus MCM development. This paper summarizes FANG structure and accomplishments and is meant to heighten community awareness of this government-led collaborative effort. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available

Research

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Open AccessArticle miRNA Profiles of Monocyte-Lineage Cells Are Consistent with Complicated Roles in HIV-1 Restriction
Viruses 2012, 4(10), 1844-1864; doi:10.3390/v4101844
Received: 25 July 2012 / Revised: 8 September 2012 / Accepted: 11 September 2012 / Published: 25 September 2012
Cited by 23 | PDF Full-text (526 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
Long-lived HIV-1 reservoirs include tissue macrophages. Monocyte-derived macrophages are more susceptible to infection and more permissive to HIV-1 replication than monocytes for reasons that may include the effects of different populations of miRNAs in these two cell classes. Specifically, miRs-28-3p, -150, -223, -198,
[...] Read more.
Long-lived HIV-1 reservoirs include tissue macrophages. Monocyte-derived macrophages are more susceptible to infection and more permissive to HIV-1 replication than monocytes for reasons that may include the effects of different populations of miRNAs in these two cell classes. Specifically, miRs-28-3p, -150, -223, -198, and -382 exert direct or indirect negative effects on HIV-1 and are reportedly downmodulated during monocyte-to-macrophage differentiation. Here, new experimental results are presented along with reviews and analysis of published studies and publicly available datasets, supporting a broader role of miRNAs in HIV-1 restriction than would be suggested by a simple and uniform downregulation of anti-HIV miRNAs during monocyte-to-macrophage differentiation. Although miR-223 is downregulated in macrophages, other putatively antiviral miRNAs are more abundant in macrophages than in monocytes or are rare and/or variably present in both cell classes. Our analyses point to the need for further studies to determine miRNA profiles of monocytes and macrophages, including classic and newly identified subpopulations; examine the sensitivity of miRNA profiling to cell isolation and differentiation protocols; and characterize rigorously the antiviral effects of previously reported and novel predicted miRNA-HIV-1 interactions in cell-specific contexts. Full article
(This article belongs to the Special Issue Viruses and miRNAs)
Open AccessArticle High Content Image Based Analysis Identifies Cell Cycle Inhibitors as Regulators of Ebola Virus Infection
Viruses 2012, 4(10), 1865-1877; doi:10.3390/v4101865
Received: 5 August 2012 / Revised: 9 September 2012 / Accepted: 11 September 2012 / Published: 25 September 2012
Cited by 8 | PDF Full-text (611 KB) | HTML Full-text | XML Full-text
Abstract
Viruses modulate a number of host biological responses including the cell cycle to favor their replication. In this study, we developed a high-content imaging (HCI) assay to measure DNA content and identify different phases of the cell cycle. We then investigated the potential
[...] Read more.
Viruses modulate a number of host biological responses including the cell cycle to favor their replication. In this study, we developed a high-content imaging (HCI) assay to measure DNA content and identify different phases of the cell cycle. We then investigated the potential effects of cell cycle arrest on Ebola virus (EBOV) infection. Cells arrested in G1 phase by serum starvation or G1/S phase using aphidicolin or G2/M phase using nocodazole showed much reduced EBOV infection compared to the untreated control. Release of cells from serum starvation or aphidicolin block resulted in a time-dependent increase in the percentage of EBOV infected cells. The effect of EBOV infection on cell cycle progression was found to be cell-type dependent. Infection of asynchronous MCF-10A cells with EBOV resulted in a reduced number of cells in G2/M phase with concomitant increase of cells in G1 phase. However, these effects were not observed in HeLa or A549 cells. Together, our studies suggest that EBOV requires actively proliferating cells for efficient replication. Furthermore, multiplexing of HCI based assays to detect viral infection, cell cycle status and other phenotypic changes in a single cell population will provide useful information during screening campaigns using siRNA and small molecule therapeutics. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessArticle Enhanced Heterosexual Transmission Hypothesis for the Origin of Pandemic HIV-1
Viruses 2012, 4(10), 1950-1983; doi:10.3390/v4101950
Received: 6 September 2012 / Revised: 15 September 2012 / Accepted: 17 September 2012 / Published: 3 October 2012
Cited by 5 | PDF Full-text (1302 KB) | HTML Full-text | XML Full-text
Abstract
HIV-1 M originated from SIVcpz endemic in chimpanzees from southeast Cameroon or neighboring areas, and it started to spread in the early 20th century. Here we examine the factors that may have contributed to simian-to-human transmission, local transmission between humans, and export to
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HIV-1 M originated from SIVcpz endemic in chimpanzees from southeast Cameroon or neighboring areas, and it started to spread in the early 20th century. Here we examine the factors that may have contributed to simian-to-human transmission, local transmission between humans, and export to a city. The region had intense ape hunting, social disruption, commercial sex work, STDs, and traffic to/from Kinshasa in the period 1899–1923. Injection treatments increased sharply around 1930; however, their frequency among local patients was far lower than among modern groups experiencing parenteral HIV-1 outbreaks. Recent molecular datings of HIV-1 M fit better the period of maximal resource exploitation and trade links than the period of high injection intensity. We conclude that although local parenteral outbreaks might have occurred, these are unlikely to have caused massive transmission. World War I led to additional, and hitherto unrecognized, risks of HIV-1 emergence. We propose an Enhanced Heterosexual Transmission Hypothesis for the origin of HIV-1 M, featuring at the time and place of its origin a coincidence of favorable co-factors (ape hunting, social disruption, STDs, and mobility) for both cross-species transmission and heterosexual spread. Our hypothesis does not exclude a role for parenteral transmission in the initial viral adaptation. Full article
(This article belongs to the Special Issue HIV Dynamics and Evolution)
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Open AccessArticle A Characterization of Aerosolized Sudan Virus Infection in African Green Monkeys, Cynomolgus Macaques, and Rhesus Macaques
Viruses 2012, 4(10), 2115-2136; doi:10.3390/v4102115
Received: 30 August 2012 / Revised: 4 October 2012 / Accepted: 4 October 2012 / Published: 15 October 2012
Cited by 12 | PDF Full-text (2290 KB) | HTML Full-text | XML Full-text
Abstract
Filoviruses are members of the genera Ebolavirus, Marburgvirus, and “Cuevavirus”. Because they cause human disease with high lethality and could potentially be used as a bioweapon, these viruses are classified as CDC Category A Bioterrorism Agents. Filoviruses are relatively stable
[...] Read more.
Filoviruses are members of the genera Ebolavirus, Marburgvirus, and “Cuevavirus”. Because they cause human disease with high lethality and could potentially be used as a bioweapon, these viruses are classified as CDC Category A Bioterrorism Agents. Filoviruses are relatively stable in aerosols, retain virulence after lyophilization, and can be present on contaminated surfaces for extended periods of time. This study explores the characteristics of aerosolized Sudan virus (SUDV) Boniface in non-human primates (NHP) belonging to three different species. Groups of cynomolgus macaques (cyno), rhesus macaques (rhesus), and African green monkeys (AGM) were challenged with target doses of 50 or 500 plaque-forming units (pfu) of aerosolized SUDV. Exposure to either viral dose resulted in increased body temperatures in all three NHP species beginning on days 4–5 post-exposure. Other clinical findings for all three NHP species included leukocytosis, thrombocytopenia, anorexia, dehydration, and lymphadenopathy. Disease in all of the NHPs was severe beginning on day 6 post-exposure, and all animals except one surviving rhesus macaque were euthanized by day 14. Serum alanine transaminase (ALT) and aspartate transaminase (AST) concentrations were elevated during the course of disease in all three species; however, AGMs had significantly higher ALT and AST concentrations than cynos and rhesus. While all three species had detectable viral load by days 3-4 post exposure, Rhesus had lower average peak viral load than cynos or AGMs. Overall, the results indicate that the disease course after exposure to aerosolized SUDV is similar for all three species of NHP. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessArticle D471G Mutation in LCMV-NP Affects Its Ability to Self-associate and Results in a Dominant Negative Effect in Viral RNA Synthesis
Viruses 2012, 4(10), 2137-2161; doi:10.3390/v4102137
Received: 9 August 2012 / Revised: 21 September 2012 / Accepted: 26 September 2012 / Published: 16 October 2012
Cited by 7 | PDF Full-text (1920 KB) | HTML Full-text | XML Full-text
Abstract
Arenaviruses merit significant interest because several family members are etiological agents of severe hemorrhagic fevers, representing a major burden to public health. Currently, there are no FDA-licensed vaccines against arenaviruses and the only available antiviral therapy is limited to the use of ribavirin
[...] Read more.
Arenaviruses merit significant interest because several family members are etiological agents of severe hemorrhagic fevers, representing a major burden to public health. Currently, there are no FDA-licensed vaccines against arenaviruses and the only available antiviral therapy is limited to the use of ribavirin that is partially effective. Arenavirus nucleoprotein (NP) is found associated with the genomic RNA forming the viral ribonucleoproteins (vRNPs) that together with the polymerase (L) direct viral replication and transcription. Virion formation requires the recruitment of vRNPs into budding sites, a process in which the arenavirus matrix-like protein (Z) plays a major role. Therefore, proper NP-NP and NP-Z interactions are required for the generation of infectious progeny. In this work we demonstrate the role of the amino acid residue D471 in the self-association of lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP). Amino acid substitutions at this position abrogate NP oligomerization, affecting its ability to mediate replication and transcription of a minigenome reporter plasmid. However, its ability to interact with the Z protein, counteract the cellular interferon response and bind to dsRNA analogs was retained. Additionally, we also document the dominant negative effect of D471G mutation on viral infection, suggesting that NP self-association is an excellent target for the development of new antivirals against arenaviruses. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessArticle Perinatal Lamb Model of Respiratory Syncytial Virus (RSV) Infection
Viruses 2012, 4(10), 2359-2378; doi:10.3390/v4102359
Received: 25 September 2012 / Revised: 17 October 2012 / Accepted: 18 October 2012 / Published: 23 October 2012
Cited by 16 | PDF Full-text (1460 KB) | HTML Full-text | XML Full-text
Abstract
Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes
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Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes infants more susceptible. The perinatal (preterm and term) lamb is a useful model of infant RSV disease as lambs have similar pulmonary structure including airway branching, Clara and type II cells, submucosal glands and Duox/lactoperoxidase (LPO) oxidative system, and prenatal alveologenesis. Lambs can be born preterm (90% gestation) and survive for experimentation although both preterm and term lambs are susceptible to ovine, bovine and human strains of RSV and develop clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions including bronchiolitis with epithelial injury, neutrophil infiltration and syncytial cell formation. RSV disease in preterm lambs is more severe than in term lambs; disease is progressively less in adults and age-dependent susceptibility is a feature similar to humans. Innate and adaptive immune responses by perinatal lambs closely parallel those of infants. The model is used to test therapeutic regimens, risk factors such as maternal ethanol consumption, and formalin inactivated RSV vaccines. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)

Review

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Open AccessReview Forty-Five Years of Marburg Virus Research
Viruses 2012, 4(10), 1878-1927; doi:10.3390/v4101878
Received: 23 August 2012 / Revised: 19 September 2012 / Accepted: 25 September 2012 / Published: 1 October 2012
Cited by 37 | PDF Full-text (2292 KB) | HTML Full-text | XML Full-text
Abstract
In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of
[...] Read more.
In 1967, the first reported filovirus hemorrhagic fever outbreak took place in Germany and the former Yugoslavia. The causative agent that was identified during this outbreak, Marburg virus, is one of the most deadly human pathogens. This article provides a comprehensive overview of our current knowledge about Marburg virus disease ranging from ecology to pathogenesis and molecular biology. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
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Open AccessReview Prevention of Cellular Suicide by Cytomegaloviruses
Viruses 2012, 4(10), 1928-1949; doi:10.3390/v4101928
Received: 31 August 2012 / Revised: 21 September 2012 / Accepted: 25 September 2012 / Published: 2 October 2012
Cited by 12 | PDF Full-text (1211 KB) | HTML Full-text | XML Full-text
Abstract
As intracellular parasites, viruses rely on many host cell functions to ensure their replication. The early induction of programmed cell death (PCD) in infected cells constitutes an effective antiviral host mechanism to restrict viral spread within an organism. As a countermeasure, viruses have
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As intracellular parasites, viruses rely on many host cell functions to ensure their replication. The early induction of programmed cell death (PCD) in infected cells constitutes an effective antiviral host mechanism to restrict viral spread within an organism. As a countermeasure, viruses have evolved numerous strategies to interfere with the induction or execution of PCD. Slowly replicating viruses such as the cytomegaloviruses (CMVs) are particularly dependent on sustained cell viability. To preserve viability, the CMVs encode several viral cell death inhibitors that target different key regulators of the extrinsic and intrinsic apoptosis pathways. The best-characterized CMV-encoded inhibitors are the viral inhibitor of caspase-8-induced apoptosis (vICA), viral mitochondrial inhibitor of apoptosis (vMIA), and viral inhibitor of Bak oligomerization (vIBO). Moreover, a viral inhibitor of RIP-mediated signaling (vIRS) that blocks programmed necrosis has been identified in the genome of murine CMV (MCMV), indicating that this cell death mode is a particularly important part of the antiviral host response. This review provides an overview of the known cell death suppressors encoded by CMVs and their mechanisms of action. Full article
(This article belongs to the Special Issue Modulation of Apoptosis by Viral Infection)
Open AccessReview Modelling the Course of an HIV Infection: Insights from Ecology and Evolution
Viruses 2012, 4(10), 1984-2013; doi:10.3390/v4101984
Received: 28 August 2012 / Revised: 19 September 2012 / Accepted: 28 September 2012 / Published: 4 October 2012
Cited by 9 | PDF Full-text (2402 KB) | HTML Full-text | XML Full-text
Abstract
The Human Immunodeficiency Virus (HIV) is one of the most threatening viral agents. This virus infects approximately 33 million people, many of whom are unaware of their status because, except for flu-like symptoms right at the beginning of the infection during the acute
[...] Read more.
The Human Immunodeficiency Virus (HIV) is one of the most threatening viral agents. This virus infects approximately 33 million people, many of whom are unaware of their status because, except for flu-like symptoms right at the beginning of the infection during the acute phase, the disease progresses more or less symptom-free for 5 to 10 years. During this asymptomatic phase, the virus slowly destroys the immune system until the onset of AIDS when opportunistic infections like pneumonia or Kaposi’s sarcoma can overcome immune defenses. Mathematical models have played a decisive role in estimating important parameters (e.g., virion clearance rate or life-span of infected cells). However, most models only account for the acute and asymptomatic latency phase and cannot explain the progression to AIDS. Models that account for the whole course of the infection rely on different hypotheses to explain the progression to AIDS. The aim of this study is to review these models, present their technical approaches and discuss the robustness of their biological hypotheses. Among the few models capturing all three phases of an HIV infection, we can distinguish between those that mainly rely on population dynamics and those that involve virus evolution. Overall, the modeling quest to capture the dynamics of an HIV infection has improved our understanding of the progression to AIDS but, more generally, it has also led to the insight that population dynamics and evolutionary processes can be necessary to explain the course of an infection. Full article
(This article belongs to the Special Issue HIV Dynamics and Evolution)
Open AccessReview Neutralizing Antibodies and Pathogenesis of Hepatitis C Virus Infection
Viruses 2012, 4(10), 2016-2030; doi:10.3390/v4102016
Received: 2 August 2012 / Revised: 28 September 2012 / Accepted: 28 September 2012 / Published: 9 October 2012
Cited by 12 | PDF Full-text (1116 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role
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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection. Full article
(This article belongs to the Special Issue Immune Evasion)
Open AccessReview Pathogenesis of Lassa Fever
Viruses 2012, 4(10), 2031-2048; doi:10.3390/v4102031
Received: 3 September 2012 / Revised: 28 September 2012 / Accepted: 3 October 2012 / Published: 9 October 2012
Cited by 27 | PDF Full-text (319 KB) | HTML Full-text | XML Full-text
Abstract
Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between
[...] Read more.
Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesis in humans and relevant animal models. Advancing knowledge significantly improves our understanding of Lassa virus biology, as well as of the mechanisms that allow the virus to evade the host’s immune system. However, further investigations are required in order to design improved diagnostic tools, an effective vaccine, and therapeutic agents. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessReview Molecular Mechanism of Arenavirus Assembly and Budding
Viruses 2012, 4(10), 2049-2079; doi:10.3390/v4102049
Received: 3 August 2012 / Revised: 25 September 2012 / Accepted: 28 September 2012 / Published: 10 October 2012
Cited by 8 | PDF Full-text (2136 KB) | HTML Full-text | XML Full-text
Abstract
Arenaviruses have a bisegmented negative-strand RNA genome, which encodes four viral proteins: GP and NP by the S segment and L and Z by the L segment. These four viral proteins possess multiple functions in infection, replication and release of progeny viruses from
[...] Read more.
Arenaviruses have a bisegmented negative-strand RNA genome, which encodes four viral proteins: GP and NP by the S segment and L and Z by the L segment. These four viral proteins possess multiple functions in infection, replication and release of progeny viruses from infected cells. The small RING finger protein, Z protein is a matrix protein that plays a central role in viral assembly and budding. Although all arenaviruses encode Z protein, amino acid sequence alignment showed a huge variety among the species, especially at the C-terminus where the L-domain is located. Recent publications have demonstrated the interactions between viral protein and viral protein, and viral protein and host cellular protein, which facilitate transportation and assembly of viral components to sites of virus egress. This review presents a summary of current knowledge regarding arenavirus assembly and budding, in comparison with other enveloped viruses. We also refer to the restriction of arenavirus production by the antiviral cellular factor, Tetherin/BST-2. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessReview HIV–1 Dynamics: A Reappraisal of Host and Viral Factors, as well as Methodological Issues
Viruses 2012, 4(10), 2080-2096; doi:10.3390/v4102080
Received: 2 August 2012 / Revised: 18 September 2012 / Accepted: 7 October 2012 / Published: 10 October 2012
Cited by 8 | PDF Full-text (414 KB) | HTML Full-text | XML Full-text
Abstract
The dynamics of HIV–1 viremia is a complex and evolving landscape with clinical and epidemiological (public health) implications. Most studies have relied on the use of set–point viral load (VL) as a readily available proxy of viral dynamics to assess host and viral
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The dynamics of HIV–1 viremia is a complex and evolving landscape with clinical and epidemiological (public health) implications. Most studies have relied on the use of set–point viral load (VL) as a readily available proxy of viral dynamics to assess host and viral correlates. This review highlights recent findings from population–based studies of set–point VL, focusing primarily on robust data related to host genetics. A comprehensive understanding of viral dynamics will clearly need to consider both host and viral characteristics, with close attention to (i) the timing of VL measurements, (ii) the biology of viral evolution, (iii) compartments of active viral replication, (iv) the transmission source partner as the immediate past microenvironment, and (v) proper application of statistical models. Full article
(This article belongs to the Special Issue HIV Dynamics and Evolution)
Open AccessReview Serological Assays Based on Recombinant Viral Proteins for the Diagnosis of Arenavirus Hemorrhagic Fevers
Viruses 2012, 4(10), 2097-2114; doi:10.3390/v4102097
Received: 1 August 2012 / Revised: 19 September 2012 / Accepted: 25 September 2012 / Published: 12 October 2012
Cited by 10 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text
Abstract
The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause
[...] Read more.
The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fever (VHF) in humans, leading to serious public health concerns. These viruses are also considered potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically in order to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as BSL-4 pathogens, thus making it difficult to develop diagnostic techniques for these virus infections in institutes without BSL-4 facilities. To overcome these difficulties, antibody detection systems in the form of an enzyme-linked immunosorbent assay (ELISA) and an indirect immunofluorescence assay were developed using recombinant nucleoproteins (rNPs) derived from these viruses. Furthermore, several antigen-detection assays were developed. For example, novel monoclonal antibodies (mAbs) to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture) ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific for detecting the respective arenavirus NPs. These rNP-based assays were proposed to be useful not only for an etiological diagnosis of VHFs, but also for seroepidemiological studies on VHFs. We recently developed arenavirus neutralization assays using vesicular stomatitis virus (VSV)-based pseudotypes bearing arenavirus recombinant glycoproteins. The goal of this article is to review the recent advances in developing laboratory diagnostic assays based on recombinant viral proteins for the diagnosis of VHFs and epidemiological studies on the VHFs caused by arenaviruses. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessReview Envelope Glycoprotein of Arenaviruses
Viruses 2012, 4(10), 2162-2181; doi:10.3390/v4102162
Received: 4 September 2012 / Revised: 5 October 2012 / Accepted: 5 October 2012 / Published: 17 October 2012
Cited by 17 | PDF Full-text (808 KB) | HTML Full-text | XML Full-text
Abstract
Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need.
[...] Read more.
Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need. Arenaviruses are comprised of two RNA genome segments and four proteins, the polymerase L, the envelope glycoprotein GP, the matrix protein Z, and the nucleoprotein NP. A crucial step in the arenavirus life-cycle is the biosynthesis and maturation of the GP precursor (GPC) by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) yielding a tripartite mature GP complex formed by GP1/GP2 and a stable signal peptide (SSP). GPC cleavage by SKI-1/S1P is crucial for fusion competence and incorporation of mature GP into nascent budding virion particles. In a first part of our review, we cover basic aspects and newer developments in the biosynthesis of arenavirus GP and its molecular interaction with SKI-1/S1P. A second part will then highlight the potential of SKI-1/S1P-mediated processing of arenavirus GPC as a novel target for therapeutic intervention to combat human pathogenic arenaviruses. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessReview Arenavirus Evasion of Host Anti-Viral Responses
Viruses 2012, 4(10), 2182-2196; doi:10.3390/v4102182
Received: 21 September 2012 / Revised: 2 October 2012 / Accepted: 10 October 2012 / Published: 17 October 2012
Cited by 5 | PDF Full-text (564 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread.
[...] Read more.
The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host’s response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessReview Hepatitis C Virus and Natural Compounds: A New Antiviral Approach?
Viruses 2012, 4(10), 2197-2217; doi:10.3390/v4102197
Received: 4 September 2012 / Revised: 2 October 2012 / Accepted: 10 October 2012 / Published: 17 October 2012
Cited by 38 | PDF Full-text (909 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C is a major global health burden with an estimated 160 million infected individuals worldwide. This long-term disease evolves slowly, often leading to chronicity and potentially to liver failure. There is no anti-HCV vaccine, and, until recently, the only treatment available, based
[...] Read more.
Hepatitis C is a major global health burden with an estimated 160 million infected individuals worldwide. This long-term disease evolves slowly, often leading to chronicity and potentially to liver failure. There is no anti-HCV vaccine, and, until recently, the only treatment available, based on pegylated interferon and ribavirin, was partially effective, and had considerable side effects. With recent advances in the understanding of the HCV life cycle, the development of promising direct acting antivirals (DAAs) has been achieved. Their use in combination with the current treatment has led to encouraging results for HCV genotype 1 patients. However, this therapy is quite expensive and will probably not be accessible for all patients worldwide. For this reason, constant efforts are being made to identify new antiviral molecules. Recent reports about natural compounds highlight their antiviral activity against HCV. Here, we aim to review the natural molecules that interfere with the HCV life cycle and discuss their potential use in HCV therapy. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview Virus-Induced Aggregates in Infected Cells
Viruses 2012, 4(10), 2218-2232; doi:10.3390/v4102218
Received: 29 August 2012 / Revised: 27 September 2012 / Accepted: 29 September 2012 / Published: 17 October 2012
Cited by 17 | PDF Full-text (1701 KB) | HTML Full-text | XML Full-text
Abstract
During infection, many viruses induce cellular remodeling, resulting in the formation of insoluble aggregates/inclusions, usually containing viral structural proteins. Identification of aggregates has become a useful diagnostic tool for certain viral infections. There is wide variety of viral aggregates, which differ by their
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During infection, many viruses induce cellular remodeling, resulting in the formation of insoluble aggregates/inclusions, usually containing viral structural proteins. Identification of aggregates has become a useful diagnostic tool for certain viral infections. There is wide variety of viral aggregates, which differ by their location, size, content and putative function. The role of aggregation in the context of a specific virus is often poorly understood, especially in the case of plant viruses. The aggregates are utilized by viruses to house a large complex of proteins of both viral and host origin to promote virus replication, translation, intra- and intercellular transportation. Aggregated structures may protect viral functional complexes from the cellular degradation machinery. Alternatively, the activation of host defense mechanisms may involve sequestration of virus components in aggregates, followed by their neutralization as toxic for the host cell. The diversity of virus-induced aggregates in mammalian and plant cells is the subject of this review. Full article
(This article belongs to the Special Issue Plant Viruses)
Open AccessReview RNA Structural Elements of Hepatitis C Virus Controlling Viral RNA Translation and the Implications for Viral Pathogenesis
Viruses 2012, 4(10), 2233-2250; doi:10.3390/v4102233
Received: 27 August 2012 / Revised: 26 September 2012 / Accepted: 1 October 2012 / Published: 19 October 2012
Cited by 22 | PDF Full-text (477 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) genome multiplication requires the concerted action of the viral RNA, host factors and viral proteins. Recent studies have provided information about the requirement of specific viral RNA motifs that play an active role in the viral life cycle. RNA regulatory
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Hepatitis C virus (HCV) genome multiplication requires the concerted action of the viral RNA, host factors and viral proteins. Recent studies have provided information about the requirement of specific viral RNA motifs that play an active role in the viral life cycle. RNA regulatory motifs controlling translation and replication of the viral RNA are mostly found at the 5' and 3' untranslated regions (UTRs). In particular, viral protein synthesis is under the control of the internal ribosome entry site (IRES) element, a complex RNA structure located at the 5'UTR that recruits the ribosomal subunits to the initiator codon. Accordingly, interfering with this RNA structural motif causes the abrogation of the viral cycle. In addition, RNA translation initiation is modulated by cellular factors, including miRNAs and RNA-binding proteins. Interestingly, a RNA structural motif located at the 3'end controls viral replication and establishes long-range RNA-RNA interactions with the 5'UTR, generating functional bridges between both ends on the viral genome. In this article, we review recent advances on virus-host interaction and translation control modulating viral gene expression in infected cells. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview Hepatitis C Virus and Cellular Stress Response: Implications to Molecular Pathogenesis of Liver Diseases
Viruses 2012, 4(10), 2251-2290; doi:10.3390/v4102251
Received: 31 August 2012 / Revised: 7 October 2012 / Accepted: 9 October 2012 / Published: 19 October 2012
Cited by 31 | PDF Full-text (2053 KB) | HTML Full-text | XML Full-text
Abstract
Infection with hepatitis C virus (HCV) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. With approximately 3% of the human population infected worldwide, HCV infection remains a global public health challenge. The efficacy of current
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Infection with hepatitis C virus (HCV) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. With approximately 3% of the human population infected worldwide, HCV infection remains a global public health challenge. The efficacy of current therapy is still limited in many patients infected with HCV, thus a greater understanding of pathogenesis in HCV infection is desperately needed. Emerging lines of evidence indicate that HCV triggers a wide range of cellular stress responses, including cell cycle arrest, apoptosis, endoplasmic reticulum (ER) stress/unfolded protein response (UPR), and autophagy. Also, recent studies suggest that these HCV-induced cellular responses may contribute to chronic liver diseases by modulating cell proliferation, altering lipid metabolism, and potentiating oncogenic pathways. However, the molecular mechanism underlying HCV infection in the pathogenesis of chronic liver diseases still remains to be determined. Here, we review the known stress response activation in HCV infection in vitro and in vivo, and also explore the possible relationship of a variety of cellular responses with the pathogenicity of HCV-associated diseases. Comprehensive knowledge of HCV-mediated disease progression shall shed new insights into the discovery of novel therapeutic targets and the development of new intervention strategy. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview Function and Regulation of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) / CRISPR Associated (Cas) Systems
Viruses 2012, 4(10), 2291-2311; doi:10.3390/v4102291
Received: 4 September 2012 / Revised: 10 October 2012 / Accepted: 11 October 2012 / Published: 19 October 2012
Cited by 44 | PDF Full-text (683 KB) | HTML Full-text | XML Full-text
Abstract
Phages are the most abundant biological entities on earth and pose a constant challenge to their bacterial hosts. Thus, bacteria have evolved numerous ‘innate’ mechanisms of defense against phage, such as abortive infection or restriction/modification systems. In contrast, the clustered regularly
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Phages are the most abundant biological entities on earth and pose a constant challenge to their bacterial hosts. Thus, bacteria have evolved numerous ‘innate’ mechanisms of defense against phage, such as abortive infection or restriction/modification systems. In contrast, the clustered regularly interspaced short palindromic repeats (CRISPR) systems provide acquired, yet heritable, sequence-specific ‘adaptive’ immunity against phage and other horizontally-acquired elements, such as plasmids. Resistance is acquired following viral infection or plasmid uptake when a short sequence of the foreign genome is added to the CRISPR array. CRISPRs are then transcribed and processed, generally by CRISPR associated (Cas) proteins, into short interfering RNAs (crRNAs), which form part of a ribonucleoprotein complex. This complex guides the crRNA to the complementary invading nucleic acid and targets this for degradation. Recently, there have been rapid advances in our understanding of CRISPR/Cas systems. In this review, we will present the current model(s) of the molecular events involved in both the acquisition of immunity and interference stages and will also address recent progress in our knowledge of the regulation of CRISPR/Cas systems. Full article
(This article belongs to the Special Issue Recent Progress in Bacteriophage Research) Print Edition available
Open AccessReview Junín Virus Pathogenesis and Virus Replication
Viruses 2012, 4(10), 2317-2339; doi:10.3390/v4102317
Received: 18 September 2012 / Revised: 2 October 2012 / Accepted: 10 October 2012 / Published: 19 October 2012
Cited by 25 | PDF Full-text (917 KB) | HTML Full-text | XML Full-text
Abstract
Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality. The virus is spread through the aerosolization of host rodent excreta and endemic to the humid pampas of Argentina. Recently, significant progress has been achieved with the development of
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Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality. The virus is spread through the aerosolization of host rodent excreta and endemic to the humid pampas of Argentina. Recently, significant progress has been achieved with the development of new technologies (e.g. reverse genetics) that have expanded knowledge about the pathogenesis and viral replication of Junín virus. We will review the pathogenesis of Junín virus in various animal models and the role of innate and adaptive immunity during infection. We will highlight current research regarding the role of molecular biology of Junín virus in elucidating virus attenuation. We will also summarize current knowledge on Junín virus pathogenesis focusing on the recent development of vaccines and potential therapeutics. Full article
(This article belongs to the Special Issue Arenaviruses)
Open AccessReview Phosphoinositides in the Hepatitis C Virus Life Cycle
Viruses 2012, 4(10), 2340-2358; doi:10.3390/v4102340
Received: 4 September 2012 / Revised: 5 October 2012 / Accepted: 9 October 2012 / Published: 19 October 2012
Cited by 19 | PDF Full-text (902 KB) | HTML Full-text | XML Full-text
Abstract
Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and
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Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and phosphatases generates distinct intracellular hubs of PIP signaling. Hepatitis C virus (HCV), like other plus-strand RNA viruses, promotes the rearrangement of intracellular membranes to assemble viral replication complexes. HCV stimulates enrichment of phosphatidylinositol 4-phosphate (PI4P) pools near endoplasmic reticulum (ER) sites by activating PI4KIIIα, the kinase responsible for generation of ER-specific PI4P pools. Inhibition of PI4KIIIα abrogates HCV replication. PI4P, the most abundant phosphoinositide, predominantly localizes to the Golgi and plays central roles in Golgi secretory functions by recruiting effector proteins involved in transport vesicle generation. The PI4P effector proteins also include the lipid-transfer and structural proteins such as ceramide transfer protein (CERT), oxysterol binding protein (OSBP) and Golgi phosphoprotein 3 (GOLPH3) that help maintain Golgi-membrane composition and structure. Depletion of Golgi-specific PI4P pools by silencing PI4KIIIβ, expression of dominant negative CERT and OSBP mutants, or silencing GOLPH3 perturb HCV secretion. In this review we highlight the role of PIPs and specifically PI4P in the HCV life cycle. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview Hiding Lipid Presentation: Viral Interference with CD1d-Restricted Invariant Natural Killer T (iNKT) Cell Activation
Viruses 2012, 4(10), 2379-2399; doi:10.3390/v4102379
Received: 2 September 2012 / Revised: 12 October 2012 / Accepted: 17 October 2012 / Published: 23 October 2012
Cited by 7 | PDF Full-text (1441 KB) | HTML Full-text | XML Full-text
Abstract
The immune system plays a major role in protecting the host against viral infection. Rapid initial protection is conveyed by innate immune cells, while adaptive immunity (including T lymphocytes) requires several days to develop, yet provides high specificity and long-lasting memory. Invariant natural
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The immune system plays a major role in protecting the host against viral infection. Rapid initial protection is conveyed by innate immune cells, while adaptive immunity (including T lymphocytes) requires several days to develop, yet provides high specificity and long-lasting memory. Invariant natural killer T (iNKT) cells are an unusual subset of T lymphocytes, expressing a semi-invariant T cell receptor together with markers of the innate NK cell lineage. Activated iNKT cells can exert direct cytolysis and can rapidly release a variety of immune-polarizing cytokines, thereby regulating the ensuing adaptive immune response. iNKT cells recognize lipids in the context of the antigen-presenting molecule CD1d. Intriguingly, CD1d-restricted iNKT cells appear to play a critical role in anti-viral defense: increased susceptibility to disseminated viral infections is observed both in patients with iNKT cell deficiency as well as in CD1d- and iNKT cell-deficient mice. Moreover, viruses have recently been found to use sophisticated strategies to withstand iNKT cell-mediated elimination. This review focuses on CD1d-restricted lipid presentation and the strategies viruses deploy to subvert this pathway. Full article
(This article belongs to the Special Issue Immune Evasion)
Open AccessReview The Baboon (Papio spp.) as a Model of Human Ebola Virus Infection
Viruses 2012, 4(10), 2400-2416; doi:10.3390/v4102400
Received: 8 October 2012 / Revised: 17 October 2012 / Accepted: 17 October 2012 / Published: 23 October 2012
Cited by 12 | PDF Full-text (476 KB) | HTML Full-text | XML Full-text
Abstract
Baboons are susceptible to natural Ebola virus (EBOV) infection and share 96% genetic homology with humans. Despite these characteristics, baboons have rarely been utilized as experimental models of human EBOV infection to evaluate the efficacy of prophylactics and therapeutics in the United States.
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Baboons are susceptible to natural Ebola virus (EBOV) infection and share 96% genetic homology with humans. Despite these characteristics, baboons have rarely been utilized as experimental models of human EBOV infection to evaluate the efficacy of prophylactics and therapeutics in the United States. This review will summarize what is known about the pathogenesis of EBOV infection in baboons compared to EBOV infection in humans and other Old World nonhuman primates. In addition, we will discuss how closely the baboon model recapitulates human EBOV infection. We will also review some of the housing requirements and behavioral attributes of baboons compared to other Old World nonhuman primates. Due to the lack of data available on the pathogenesis of Marburg virus (MARV) infection in baboons, discussion of the pathogenesis of MARV infection in baboons will be limited. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available

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Open AccessCorrection Brockman, M.A., et al., Human Leukocyte Antigen (HLA) Class I Down-Regulation by Human Immunodeficiency Virus Type 1 Negative Factor (HIV-1 Nef): What Might We Learn From Natural Sequence Variants? Viruses 2012, 4, 1711-1730
Viruses 2012, 4(10), 2014-2015; doi:10.3390/v4102014
Received: 4 October 2012 / Revised: 5 October 2012 / Accepted: 5 October 2012 / Published: 5 October 2012
Cited by 1 | PDF Full-text (386 KB) | HTML Full-text | XML Full-text
Abstract In the original manuscript, the text in figure 1 is illegible. Furthermore, there is an unnecessary carriage return (page 1716, ~line 18) "crystallographic ... methods". [...] Full article
(This article belongs to the Special Issue Immune Evasion)
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