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Viruses, Volume 6, Issue 4 (April 2014), Pages 1473-1875

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Research

Jump to: Review, Other

Open AccessArticle The Carboxy Terminal Region of the Human Cytomegalovirus Immediate Early 1 (IE1) Protein Disrupts Type II Inteferon Signaling
Viruses 2014, 6(4), 1502-1524; doi:10.3390/v6041502
Received: 31 December 2013 / Revised: 7 March 2014 / Accepted: 7 March 2014 / Published: 2 April 2014
Cited by 1 | PDF Full-text (912 KB) | HTML Full-text | XML Full-text
Abstract
Interferons (IFNs) activate the first lines of defense against viruses, and promote innate and adaptive immune responses to viruses. We report that the immediate early 1 (IE1) protein of human cytomegalovirus (HCMV) disrupts signaling by IFNγ. The carboxyl-terminal region of IE1 is [...] Read more.
Interferons (IFNs) activate the first lines of defense against viruses, and promote innate and adaptive immune responses to viruses. We report that the immediate early 1 (IE1) protein of human cytomegalovirus (HCMV) disrupts signaling by IFNγ. The carboxyl-terminal region of IE1 is required for this function. We found no defect in the initial events in IFNγ signaling or in nuclear accumulation of signal transducer and activator of transcription 1 (STAT1) in IE1-expressing cells. Moreover, we did not observe an association between disruption of IFNγ signaling and nuclear domain 10 (ND10) disruption. However, there is reduced binding of STAT1 homodimers to target gamma activated sequence (GAS) elements in the presence of IE1. Co-immunoprecipitation studies failed to support a direct interaction between IE1 and STAT1, although these studies revealed that the C-terminal region of IE1 was required for interaction with STAT2. Together, these results indicate that IE1 disrupts IFNγ signaling by interfering with signaling events in the nucleus through a novel mechanism. Full article
(This article belongs to the Special Issue Recent CMV Research) Print Edition available
Open AccessArticle Comprehensive Characterization of Serum MicroRNA Profile in Response to the Emerging Avian Influenza A (H7N9) Virus Infection in Humans
Viruses 2014, 6(4), 1525-1539; doi:10.3390/v6041525
Received: 31 December 2013 / Revised: 13 February 2014 / Accepted: 18 March 2014 / Published: 2 April 2014
Cited by 17 | PDF Full-text (951 KB) | HTML Full-text | XML Full-text
Abstract
A novel avian-origin influenza A (H7N9) virus recently occurred in China and caused 137 human infection cases with a 32.8% mortality rate. Although various detection procedures have been developed, the pathogenesis of this emerging virus in humans remains largely unknown. In this [...] Read more.
A novel avian-origin influenza A (H7N9) virus recently occurred in China and caused 137 human infection cases with a 32.8% mortality rate. Although various detection procedures have been developed, the pathogenesis of this emerging virus in humans remains largely unknown. In this study, we characterized serum microRNA (miRNA) profile in response to H7N9 virus infection using TaqMan Low Density Arrays. Upon infection, a total of 395 miRNAs were expressed in the serum pool of patients, far beyond the 221 in healthy controls. Among the 187 commonly expressed miRNAs, 146 were up-regulated and only 7 down-regulated in patients. Further analysis by quantitative RT-PCR revealed that the serum levels of miR-17, miR-20a, miR-106a and miR-376c were significantly elevated in patients compared with healthy individuals (p < 0.05). Receiver operating characteristic (ROC) curves were constructed to show that each miRNA could discriminate H7N9 patients from controls with area under the curve (AUC) values ranging from 0.622 to 0.898, whereas a combination of miR-17, miR-20a, miR-106a and miR-376c obtained a higher discriminating ability with an AUC value of 0.96. Our findings unravel the significant alterations in serum miRNA expression following virus infection and manifest great potential of circulating miRNAs for the diagnosis of viral diseases. Full article
(This article belongs to the Special Issue Viruses and miRNAs)
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Open AccessArticle Generation of Recombinant Rabies Virus CVS-11 Expressing eGFP Applied to the Rapid Virus Neutralization Test
Viruses 2014, 6(4), 1578-1589; doi:10.3390/v6041578
Received: 6 January 2014 / Revised: 26 February 2014 / Accepted: 13 March 2014 / Published: 4 April 2014
Cited by 5 | PDF Full-text (689 KB) | HTML Full-text | XML Full-text
Abstract
The determination of levels of rabies virus-neutralizing antibody (VNA) provides the foundation for the quantitative evaluation of immunity effects. The traditional fluorescent antibody virus neutralization test (FAVN) using a challenge virus standard (CVS)-11 strain as a detection antigen and staining infected cells [...] Read more.
The determination of levels of rabies virus-neutralizing antibody (VNA) provides the foundation for the quantitative evaluation of immunity effects. The traditional fluorescent antibody virus neutralization test (FAVN) using a challenge virus standard (CVS)-11 strain as a detection antigen and staining infected cells with a fluorescein isothiocyanate (FITC)-labeled monoclonal antibody, is expensive and high-quality reagents are often difficult to obtain in developing countries. Indeed, it is essential to establish a rapid, economical, and specific rabies virus neutralization test (VNT). Here, we describe a recombinant virus rCVS-11-eGFP strain that stably expresses enhanced green fluorescent protein (eGFP) based on a reverse genetic system of the CVS-11 strain. Compared to the rCVS-11 strain, the rCVS-11-eGFP strain showed a similar growth property with passaging stability in vitro and pathogenicity in vivo. The rCVS-11-eGFP strain was utilized as a detection antigen to determine the levels of rabies VNAs in 23 human and 29 canine sera; this technique was termed the FAVN-eGFP method. The good reproducibility of FAVN-eGFP was tested with partial serum samples. Neutralization titers obtained from FAVN and FAVN-eGFP were not significantly different. The FAVN-eGFP method allows rapid economical, specific, and high-throughput assessment for the titration of rabies VNAs. Full article
(This article belongs to the Section Animal Viruses)
Open AccessArticle Superresolution Imaging of Human Cytomegalovirus vMIA Localization in Sub-Mitochondrial Compartments
Viruses 2014, 6(4), 1612-1636; doi:10.3390/v6041612
Received: 17 January 2014 / Revised: 16 March 2014 / Accepted: 27 March 2014 / Published: 9 April 2014
Cited by 5 | PDF Full-text (2338 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The human cytomegalovirus (HCMV) viral mitochondria-localized inhibitor of apoptosis (vMIA) protein, traffics to mitochondria-associated membranes (MAM), where the endoplasmic reticulum (ER) contacts the outer mitochondrial membrane (OMM). vMIA association with the MAM has not been visualized by imaging. Here, we have visualized [...] Read more.
The human cytomegalovirus (HCMV) viral mitochondria-localized inhibitor of apoptosis (vMIA) protein, traffics to mitochondria-associated membranes (MAM), where the endoplasmic reticulum (ER) contacts the outer mitochondrial membrane (OMM). vMIA association with the MAM has not been visualized by imaging. Here, we have visualized this by using a combination of confocal and superresolution imaging. Deconvolution of confocal microscopy images shows vMIA localizes away from mitochondrial matrix at the Mitochondria-ER interface. By gated stimulated emission depletion (GSTED) imaging, we show that along this interface vMIA is distributed in clusters. Through multicolor, multifocal structured illumination microscopy (MSIM), we find vMIA clusters localize away from MitoTracker Red, indicating its OMM localization. GSTED and MSIM imaging show vMIA exists in clusters of ~100–150 nm, which is consistent with the cluster size determined by Photoactivated Localization Microscopy (PALM). With these diverse superresolution approaches, we have imaged the clustered distribution of vMIA at the OMM adjacent to the ER. Our findings directly compare the relative advantages of each of these superresolution imaging modalities for imaging components of the MAM and sub-mitochondrial compartments. These studies establish the ability of superresolution imaging to provide valuable insight into viral protein location, particularly in the sub-mitochondrial compartments, and into their clustered organization. Full article
(This article belongs to the Special Issue Recent CMV Research) Print Edition available
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Open AccessArticle Generation of West Nile Virus Infectious Clones Containing Amino Acid Insertions Between Capsid and Capsid Anchor
Viruses 2014, 6(4), 1637-1653; doi:10.3390/v6041637
Received: 4 February 2014 / Revised: 19 March 2014 / Accepted: 21 March 2014 / Published: 9 April 2014
Cited by 6 | PDF Full-text (2988 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
West Nile virus (WNV) is a positive-sense RNA arbovirus responsible for recent outbreaks of severe neurological disease within the US and Europe. Large-scale analyses of antiviral compounds that inhibit virus replication have been limited due to the lack of an adequate WN [...] Read more.
West Nile virus (WNV) is a positive-sense RNA arbovirus responsible for recent outbreaks of severe neurological disease within the US and Europe. Large-scale analyses of antiviral compounds that inhibit virus replication have been limited due to the lack of an adequate WN reporter virus. Previous attempts to insert a reporter into the 3’ untranslated region of WNV generated unstable viruses, suggesting that this region does not accommodate additional nucleotides. Here, we engineered two WNV infectious clones containing insertions at the Capsid (C)/Capsid Anchor (CA) junction of the viral polyprotein. Recombinant viruses containing a TAT(1-67) or Gaussia Luciferase (GLuc) gene at this location were successfully recovered. However, rapid loss of most, if not all, of the reporter sequence occurred for both viruses, indicating that the reporter viruses were not stable. While the GLuc viruses predominantly reverted back to wild-type WNV length, the TAT viruses retained up to 75 additional nucleotides of the reporter sequence. These additional nucleotides were stable over at least five passages and did not significantly alter WNV fitness. Thus, the C/CA junction of WNV can tolerate additional nucleotides, though insertions are subject to certain constraints. Full article
(This article belongs to the Section Animal Viruses)
Open AccessArticle Analysis of Determinants in Filovirus Glycoproteins Required for Tetherin Antagonism
Viruses 2014, 6(4), 1654-1671; doi:10.3390/v6041654
Received: 25 November 2013 / Revised: 27 March 2014 / Accepted: 30 March 2014 / Published: 9 April 2014
Cited by 6 | PDF Full-text (1763 KB) | HTML Full-text | XML Full-text
Abstract
The host cell protein tetherin can restrict the release of enveloped viruses from infected cells. The HIV-1 protein Vpu counteracts tetherin by removing it from the site of viral budding, the plasma membrane, and this process depends on specific interactions between the [...] Read more.
The host cell protein tetherin can restrict the release of enveloped viruses from infected cells. The HIV-1 protein Vpu counteracts tetherin by removing it from the site of viral budding, the plasma membrane, and this process depends on specific interactions between the transmembrane domains of Vpu and tetherin. In contrast, the glycoproteins (GPs) of two filoviruses, Ebola and Marburg virus, antagonize tetherin without reducing surface expression, and the domains in GP required for tetherin counteraction are unknown. Here, we show that filovirus GPs depend on the presence of their authentic transmembrane domains for virus-cell fusion and tetherin antagonism. However, conserved residues within the transmembrane domain were dispensable for membrane fusion and tetherin counteraction. Moreover, the insertion of the transmembrane domain into a heterologous viral GP, Lassa virus GPC, was not sufficient to confer tetherin antagonism to the recipient. Finally, mutation of conserved residues within the fusion peptide of Ebola virus GP inhibited virus-cell fusion but did not ablate tetherin counteraction, indicating that the fusion peptide and the ability of GP to drive host cell entry are not required for tetherin counteraction. These results suggest that the transmembrane domains of filoviral GPs contribute to tetherin antagonism but are not the sole determinants. Full article
(This article belongs to the collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
Open AccessCommunication Muju Virus, Harbored by Myodes regulus in Korea, Might Represent a Genetic Variant of Puumala Virus, the Prototype Arvicolid Rodent-Borne Hantavirus
Viruses 2014, 6(4), 1701-1714; doi:10.3390/v6041701
Received: 9 December 2013 / Revised: 20 March 2014 / Accepted: 21 March 2014 / Published: 14 April 2014
Cited by 5 | PDF Full-text (1041 KB) | HTML Full-text | XML Full-text
Abstract
The genome of Muju virus (MUJV), identified originally in the royal vole (Myodes regulus) in Korea, was fully sequenced to ascertain its genetic and phylogenetic relationship with Puumala virus (PUUV), harbored by the bank vole (My. glareolus), and [...] Read more.
The genome of Muju virus (MUJV), identified originally in the royal vole (Myodes regulus) in Korea, was fully sequenced to ascertain its genetic and phylogenetic relationship with Puumala virus (PUUV), harbored by the bank vole (My. glareolus), and a PUUV-like virus, named Hokkaido virus (HOKV), in the grey red-backed vole (My. rufocanus) in Japan. Whole genome sequence analysis of the 6544-nucleotide large (L), 3652-nucleotide medium (M) and 1831-nucleotide small (S) segments of MUJV, as well as the amino acid sequences of their gene products, indicated that MUJV strains from different capture sites might represent genetic variants of PUUV, the prototype arvicolid rodent-borne hantavirus in Europe. Distinct geographic-specific clustering of MUJV was found in different provinces in Korea, and phylogenetic analyses revealed that MUJV and HOKV share a common ancestry with PUUV. A better understanding of the taxonomic classification and pathogenic potential of MUJV must await its isolation in cell culture. Full article
(This article belongs to the Special Issue Hantaviruses)
Open AccessCommunication High-Level Systemic Expression of Conserved Influenza Epitope in Plants on the Surface of Rod-Shaped Chimeric Particles
Viruses 2014, 6(4), 1789-1800; doi:10.3390/v6041789
Received: 20 November 2013 / Revised: 10 March 2014 / Accepted: 1 April 2014 / Published: 21 April 2014
Cited by 4 | PDF Full-text (3137 KB) | HTML Full-text | XML Full-text
Abstract
Recombinant viruses based on the cDNA copy of the tobacco mosaic virus (TMV) genome carrying different versions of the conserved M2e epitope from influenza virus A cloned into the coat protein (CP) gene were obtained and partially characterized by our group previously; [...] Read more.
Recombinant viruses based on the cDNA copy of the tobacco mosaic virus (TMV) genome carrying different versions of the conserved M2e epitope from influenza virus A cloned into the coat protein (CP) gene were obtained and partially characterized by our group previously; cysteines in the human consensus M2e sequence were changed to serine residues. This work intends to show some biological properties of these viruses following plant infections. Agroinfiltration experiments on Nicotiana benthamiana confirmed the efficient systemic expression of M2e peptides, and two point amino acid substitutions in recombinant CPs significantly influenced the symptoms and development of viral infections. Joint expression of RNA interference suppressor protein p19 from tomato bushy stunt virus (TBSV) did not affect the accumulation of CP-M2e-ser recombinant protein in non-inoculated leaves. RT-PCR analysis of RNA isolated from either infected leaves or purified TMV-M2e particles proved the genetic stability of TMV‑based viral vectors. Immunoelectron microscopy of crude plant extracts demonstrated that foreign epitopes are located on the surface of chimeric virions. The rod‑shaped geometry of plant-produced M2e epitopes is different from the icosahedral or helical filamentous arrangement of M2e antigens on the carrier virus-like particles (VLP) described earlier. Thereby, we created a simple and efficient system that employs agrobacteria and plant viral vectors in order to produce a candidate broad-spectrum flu vaccine. Full article
(This article belongs to the Special Issue Feature Papers)
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Open AccessArticle Dysregulated microRNA Expression in Serum of Non-Vaccinated Children with Varicella
Viruses 2014, 6(4), 1823-1836; doi:10.3390/v6041823
Received: 27 November 2013 / Revised: 25 March 2014 / Accepted: 9 April 2014 / Published: 22 April 2014
Cited by 5 | PDF Full-text (783 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Circulating microRNAs (miRNAs) may play an important role in pathogen-host interactions and can serve as molecular markers for the detection of infectious diseases. To date, the relationship between circulating miRNAs and varicella-zoster virus (VZV) caused varicella has not been reported. Using TaqMan [...] Read more.
Circulating microRNAs (miRNAs) may play an important role in pathogen-host interactions and can serve as molecular markers for the detection of infectious diseases. To date, the relationship between circulating miRNAs and varicella-zoster virus (VZV) caused varicella has not been reported. Using TaqMan Low-Density Array (TLDA) analysis, expression levels of miRNAs in serum samples from 29 patients with varicella and 60 patients with Bordetella pertussis (BP), measles virus (MEV) and enterovirus (EV) were analyzed. The array results showed that 247 miRNAs were differentially expressed in sera of the varicella patients compared with healthy controls (215 up-regulated and 32 down-regulated). Through the following qRT-PCR confirmation and receiver operational characteristic (ROC) curve analysis, five miRNAs (miR-197, miR-629, miR-363, miR-132 and miR-122) were shown to distinguish varicella patients from healthy controls and other microbial infections with moderate sensitivity and specificity. A number of significantly enriched pathways regulated by these circulating miRNAs were predicted, and some of them were involved in inflammatory response, nervous system and respiratory system development. Our results, for the first time, revealed that a number of miRNAs were differentially expressed during VZV infection, and these five serum miRNAs have great potential to serve as biomarkers for the diagnosis of VZV infection in varicella patients. Full article
(This article belongs to the Special Issue Viruses and miRNAs)
Open AccessArticle Characterization of the Anti-Influenza Activity of the Chinese Herbal Plant Paeonia lactiflora
Viruses 2014, 6(4), 1861-1875; doi:10.3390/v6041861
Received: 2 January 2014 / Revised: 20 March 2014 / Accepted: 8 April 2014 / Published: 23 April 2014
Cited by 4 | PDF Full-text (880 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bai Shao (BS, the root of Paeonia lactiflora Pall.), a common Chinese herb in many recipes used to treat viral infection and liver diseases, is recognized for its ability to nourish menstruation, its Yin convergence, and as an antiperspirant. However, the mechanism [...] Read more.
Bai Shao (BS, the root of Paeonia lactiflora Pall.), a common Chinese herb in many recipes used to treat viral infection and liver diseases, is recognized for its ability to nourish menstruation, its Yin convergence, and as an antiperspirant. However, the mechanism and components for its antiviral function remain to be elucidated. In this study, an ethanolic extract of BS was further partitioned into aqueous and organic parts (EAex) for in vitro functional study and in vivo efficacy testing. EAex exhibited an IC50 of 0.016 ± 0.005 mg/mL against influenza virus A/WSN/33 (H1N1), with broad-spectrum inhibitory activity against different strains of human influenza A viruses, including clinical oseltamivir-resistant isolates and an H1N1pdm strain. The synthesis of both viral RNA and protein was profoundly inhibited when the cells were treated with EAex. A time-of-addition assay demonstrated that EAex exerted its antiviral activity at various stages of the virus replication cycle. We addressed its antiviral activity at virus entry and demonstrated that EAex inhibits viral hemagglutination and viral binding to and penetration into host cells. In vivo animal testing showed that 200 mg/kg/d of EAex offered significant protection against viral infection. We conclude that BS possesses antiviral activity and has the potential for development as an anti-influenza agent. Full article
(This article belongs to the Section Antivirals & Vaccines)

Review

Jump to: Research, Other

Open AccessReview Using the Nonhuman Primate Model of HCMV to Guide Vaccine Development
Viruses 2014, 6(4), 1483-1501; doi:10.3390/v6041483
Received: 7 February 2014 / Revised: 11 March 2014 / Accepted: 12 March 2014 / Published: 27 March 2014
Cited by 5 | PDF Full-text (574 KB) | HTML Full-text | XML Full-text
Abstract
The natural history of human cytomegalovirus (HCMV) is inextricably associated with mucosal surfaces. The vast preponderance of primary infections occur following mucosal exposure to infectious virions, and the high seroprevalence of HCMV throughout the world is due to long-term excretion of HCMV [...] Read more.
The natural history of human cytomegalovirus (HCMV) is inextricably associated with mucosal surfaces. The vast preponderance of primary infections occur following mucosal exposure to infectious virions, and the high seroprevalence of HCMV throughout the world is due to long-term excretion of HCMV in bodily fluids from multiple mucosal sites. Accumulating evidence presents a model where the earliest virus-host interactions following infection dictate the long-term pattern of infection, alter innate immune responses that skew adaptive responses to enable persistence within an immune host, and are essential for reinfection of a host with prior immunity. HCMV has evolved a complex repertoire of viral functions fine-tuned to manipulate the immune environment both locally at the sites of infection and systemically within an infected host. Collectively, viral immune modulation represents a significant impediment for an HCMV vaccine. As HCMV can disseminate beyond mucosal surfaces to reinfect immune hosts, it may not matter whether prior immunity results from prior infection or immunization. A better understanding of the earliest virus-hosts interactions at mucosal surfaces may identify elements of the viral proteome that are especially susceptible to vaccine-mediated disruption and prevent challenge virus from disseminating to distal sites, particularly the maternal-fetal interface. Full article
(This article belongs to the Special Issue Recent CMV Research) Print Edition available
Open AccessReview Peptide-Based Technologies to Alter Adenoviral Vector Tropism: Ways and Means for Systemic Treatment of Cancer
Viruses 2014, 6(4), 1540-1563; doi:10.3390/v6041540
Received: 10 February 2014 / Revised: 15 March 2014 / Accepted: 20 March 2014 / Published: 2 April 2014
Cited by 6 | PDF Full-text (647 KB) | HTML Full-text | XML Full-text
Abstract
Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Meanwhile, the most important challenge is to develop gene [...] Read more.
Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Meanwhile, the most important challenge is to develop gene delivery vectors with high efficiency through target cell selectivity, in particular under in situ conditions. The most widely used vector system to transduce cells is based on adenovirus (Ad). Recent endeavors in the development of selective Ad vectors that target cells or tissues of interest and spare the alteration of all others have focused on the modification of the virus broad natural tropism. A popular way of Ad targeting is achieved by directing the vector towards distinct cellular receptors. Redirecting can be accomplished by linking custom-made peptides with specific affinity to cellular surface proteins via genetic integration, chemical coupling or bridging with dual-specific adapter molecules. Ideally, targeted vectors are incapable of entering cells via their native receptors. Such altered vectors offer new opportunities to delineate functional genomics in a natural environment and may enable efficient systemic therapeutic approaches. This review provides a summary of current state-of-the-art techniques to specifically target adenovirus-based gene delivery vectors. Full article
(This article belongs to the Special Issue Adenoviral Vectors)
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Open AccessReview Poxviruses in Bats … so What?
Viruses 2014, 6(4), 1564-1577; doi:10.3390/v6041564
Received: 28 January 2014 / Revised: 13 March 2014 / Accepted: 17 March 2014 / Published: 3 April 2014
Cited by 3 | PDF Full-text (789 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Poxviruses are important pathogens of man and numerous domestic and wild animal species. Cross species (including zoonotic) poxvirus infections can have drastic consequences for the recipient host. Bats are a diverse order of mammals known to carry lethal viral zoonoses such as [...] Read more.
Poxviruses are important pathogens of man and numerous domestic and wild animal species. Cross species (including zoonotic) poxvirus infections can have drastic consequences for the recipient host. Bats are a diverse order of mammals known to carry lethal viral zoonoses such as Rabies, Hendra, Nipah, and SARS. Consequent targeted research is revealing bats to be infected with a rich diversity of novel viruses. Poxviruses were recently identified in bats and the settings in which they were found were dramatically different. Here, we review the natural history of poxviruses in bats and highlight the relationship of the viruses to each other and their context in the Poxviridae family. In addition to considering the zoonotic potential of these viruses, we reflect on the broader implications of these findings. Specifically, the potential to explore and exploit this newfound relationship to study coevolution and cross species transmission together with fundamental aspects of poxvirus host tropism as well as bat virology and immunology. Full article
(This article belongs to the Special Issue Viruses and Bats)
Open AccessReview Occult HBV Infection: A Faceless Enemy in Liver Cancer Development
Viruses 2014, 6(4), 1590-1611; doi:10.3390/v6041590
Received: 31 January 2014 / Revised: 13 March 2014 / Accepted: 20 March 2014 / Published: 8 April 2014
Cited by 2 | PDF Full-text (1040 KB) | HTML Full-text | XML Full-text
Abstract
The hepatitis B virus (HBV) represents a worldwide public health problem; the virus is present in one third of the global population. However, this rate may in fact be higher due to occult hepatitis B virus infection (OBI). This condition is characterized [...] Read more.
The hepatitis B virus (HBV) represents a worldwide public health problem; the virus is present in one third of the global population. However, this rate may in fact be higher due to occult hepatitis B virus infection (OBI). This condition is characterized by the presence of the viral genome in the liver of individuals sero-negative for the virus surface antigen (HBsAg). The causes of the absence of HBsAg in serum are unknown, however, mutations have been identified that produce variants not recognized by current immunoassays. Epigenetic and immunological host mechanisms also appear to be involved in HBsAg suppression. Current evidence suggests that OBI maintains its carcinogenic potential, favoring the progression of fibrosis and cirrhosis of the liver. In common with open HBV infection, OBI can contribute to the establishment of hepatocellular carcinoma. Epidemiological data regarding the global prevalence of OBI vary due to the use of detection methods of different sensitivity and specificity. In Latin America, which is considered an area of low prevalence for HBV, diagnostic screening methods using gene amplification tests for confirmation of OBI are not conducted. This prevents determination of the actual prevalence of OBI, highlighting the need for the implementation of cutting edge technology in epidemiological surveillance systems. Full article
(This article belongs to the collection Current Threats and Findings in Virology)
Open AccessReview Matrix and Backstage: Cellular Substrates for Viral Vaccines
Viruses 2014, 6(4), 1672-1700; doi:10.3390/v6041672
Received: 31 January 2014 / Revised: 28 March 2014 / Accepted: 2 April 2014 / Published: 11 April 2014
Cited by 4 | PDF Full-text (756 KB) | HTML Full-text | XML Full-text
Abstract
Vaccines are complex products that are manufactured in highly dynamic processes. Cellular substrates are one critical component that can have an enormous impact on reactogenicity of the final preparation, level of attenuation of a live virus, yield of infectious units or antigens, [...] Read more.
Vaccines are complex products that are manufactured in highly dynamic processes. Cellular substrates are one critical component that can have an enormous impact on reactogenicity of the final preparation, level of attenuation of a live virus, yield of infectious units or antigens, and cost per vaccine dose. Such parameters contribute to feasibility and affordability of vaccine programs both in industrialized countries and developing regions. This review summarizes the diversity of cellular substrates for propagation of viral vaccines from primary tissue explants and embryonated chicken eggs to designed continuous cell lines of human and avian origin. Full article
(This article belongs to the Special Issue Virus-based Vaccines)
Open AccessReview HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies
Viruses 2014, 6(4), 1715-1758; doi:10.3390/v6041715
Received: 2 January 2014 / Revised: 18 March 2014 / Accepted: 20 March 2014 / Published: 14 April 2014
Cited by 18 | PDF Full-text (2110 KB) | HTML Full-text | XML Full-text
Abstract
The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host [...] Read more.
The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host immune system and unaffected by existing antiviral drugs. Rebound of viremia and recovery of systemic infection that follows interruption of therapy, necessitates life-long treatments with problems of compliance, toxicity, and untenable costs, especially in developing countries where the infection hits worst. Extensive research efforts have led to the proposal and preliminary testing of several anti-latency compounds, however, overall, eradication strategies have had, so far, limited clinical success while posing several risks for patients. This review will briefly summarize the more recent advances in the elucidation of mechanisms that regulates the establishment/maintenance of latency and therapeutic strategies currently under evaluation in order to eradicate HIV persistence. Full article
(This article belongs to the Special Issue HIV Latency)
Open AccessReview Filoviruses in Bats: Current Knowledge and Future Directions
Viruses 2014, 6(4), 1759-1788; doi:10.3390/v6041759
Received: 1 February 2014 / Revised: 1 April 2014 / Accepted: 2 April 2014 / Published: 17 April 2014
Cited by 51 | PDF Full-text (1421 KB) | HTML Full-text | XML Full-text
Abstract
Filoviruses, including Ebolavirus and Marburgvirus, pose significant threats to public health and species conservation by causing hemorrhagic fever outbreaks with high mortality rates. Since the first outbreak in 1967, their origins, natural history, and ecology remained elusive until recent studies linked [...] Read more.
Filoviruses, including Ebolavirus and Marburgvirus, pose significant threats to public health and species conservation by causing hemorrhagic fever outbreaks with high mortality rates. Since the first outbreak in 1967, their origins, natural history, and ecology remained elusive until recent studies linked them through molecular, serological, and virological studies to bats. We review the ecology, epidemiology, and natural history of these systems, drawing on examples from other bat-borne zoonoses, and highlight key areas for future research. We compare and contrast results from ecological and virological studies of bats and filoviruses with those of other systems. We also highlight how advanced methods, such as more recent serological assays, can be interlinked with flexible statistical methods and experimental studies to inform the field studies necessary to understand filovirus persistence in wildlife populations and cross-species transmission leading to outbreaks. We highlight the need for a more unified, global surveillance strategy for filoviruses in wildlife, and advocate for more integrated, multi-disciplinary approaches to understand dynamics in bat populations to ultimately mitigate or prevent potentially devastating disease outbreaks. Full article
(This article belongs to the Special Issue Viruses and Bats)
Open AccessReview Hantavirus Gn and Gc Envelope Glycoproteins: Key Structural Units for Virus Cell Entry and Virus Assembly
Viruses 2014, 6(4), 1801-1822; doi:10.3390/v6041801
Received: 3 January 2014 / Revised: 20 March 2014 / Accepted: 31 March 2014 / Published: 21 April 2014
Cited by 9 | PDF Full-text (1007 KB) | HTML Full-text | XML Full-text
Abstract
In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed [...] Read more.
In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed by Gn and Gc envelope glycoproteins. In this review, current knowledge of the Gn and Gc structures and their functions in virus cell entry and exit is summarized. During virus cell entry, the role of Gn and Gc in receptor binding has not yet been determined. Nevertheless, biochemical studies suggest that the subsequent virus-membrane fusion activity is accomplished by Gc. Further, a class II fusion protein conformation has been predicted for Gc of hantaviruses, and novel crystallographic data confirmed such a fold for the Rift Valley fever virus (RVFV) Gc protein. During virus cell exit, the assembly of different viral components seems to be established by interaction of Gn and Gc cytoplasmic tails (CT) with internal viral ribonucleocapsids. Moreover, recent findings show that hantavirus glycoproteins accomplish important roles during virus budding since they self-assemble into virus-like particles. Collectively, these novel insights provide essential information for gaining a more detailed understanding of Gn and Gc functions in the early and late steps of the hantavirus infection cycle. Full article
(This article belongs to the Special Issue Hantaviruses)
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Open AccessReview HIV-1 Latency in Monocytes/Macrophages
Viruses 2014, 6(4), 1837-1860; doi:10.3390/v6041837
Received: 2 January 2014 / Revised: 11 March 2014 / Accepted: 28 March 2014 / Published: 22 April 2014
Cited by 35 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text
Abstract
Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established [...] Read more.
Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART) has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host. Full article
(This article belongs to the Special Issue HIV Latency)

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Open AccessShort Communication Characterization of Juquitiba Virus in Oligoryzomys fornesi from Brazilian Cerrado
Viruses 2014, 6(4), 1473-1482; doi:10.3390/v6041473
Received: 15 October 2013 / Revised: 30 November 2013 / Accepted: 17 December 2013 / Published: 26 March 2014
Cited by 3 | PDF Full-text (280 KB) | HTML Full-text | XML Full-text
Abstract
The Juquitiba virus, an agent of Hantavirus Cardiopulmonary Syndrome, is one of the most widely distributed hantavirus found in South America. It has been detected in Oligoryzomys nigripes, Akodon montensis, Oxymycterus judex, Akodon paranaensis in Brazil and in O. [...] Read more.
The Juquitiba virus, an agent of Hantavirus Cardiopulmonary Syndrome, is one of the most widely distributed hantavirus found in South America. It has been detected in Oligoryzomys nigripes, Akodon montensis, Oxymycterus judex, Akodon paranaensis in Brazil and in O. nigripes, Oryzomys sp. and Oligoryzomys fornesi rodents in Argentine, Paraguay and Uruguay. Here, we report the genomic characterization of the complete S segment from the Juquitiba strain, isolated from the lung tissues of O. fornesi, the presumed rodent reservoir of Anajatuba virus in Brazilian Amazon, captured in the Cerrado Biome, Brazil. Full article
(This article belongs to the Special Issue Hantaviruses)

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