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Viruses, Volume 4, Issue 12 (December 2012), Pages 3270-3952

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Research

Jump to: Review, Other

Open AccessArticle Subtype Specific Differences in NS5A Domain II Reveals Involvement of Proline at Position 310 in Cyclosporine Susceptibility of Hepatitis C Virus
Viruses 2012, 4(12), 3303-3315; doi:10.3390/v4123303
Received: 11 October 2012 / Revised: 17 November 2012 / Accepted: 20 November 2012 / Published: 22 November 2012
Cited by 9 | PDF Full-text (699 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) is susceptible to cyclosporine (CsA) and other cyclophilin (CypA) inhibitors, but the genetic basis of susceptibility is controversial. Whether genetic variation in NS5A alters cell culture susceptibility of HCV to CypA inhibition is unclear. We constructed replicons containing [...] Read more.
Hepatitis C virus (HCV) is susceptible to cyclosporine (CsA) and other cyclophilin (CypA) inhibitors, but the genetic basis of susceptibility is controversial. Whether genetic variation in NS5A alters cell culture susceptibility of HCV to CypA inhibition is unclear. We constructed replicons containing NS5A chimeras from genotypes 1a, 2a and 4a to test how variation in carboxy terminal regions of NS5A altered the genotype 1b CsA susceptibility. All chimeric replicons including genotype 1b Con1LN-wt replicon exhibited some cell culture sensitivity to CsA with genotype 4a being most sensitive and 1a the least. The CypA binding pattern of truncated NS5A genotypes correlated with the susceptibility of these replicons to CsA. The Con1LN-wt replicon showed increased susceptibility towards CsA when proline at position 310P was mutated to either threonine or alanine. Furthermore, a 15 amino acid long peptide fused N terminally to GFP coding sequences confirmed involvement of proline at 310 in CypA binding. Our findings are consistent with CypA acting on multiple prolines outside of the previously identified CypA binding sites. These results suggest multiple specific genetic variants between genotype 1a and 1b in the C-terminus of NS5A alter the CsA susceptibility of replicons, and some variants may oppose the effects of others. Full article
(This article belongs to the Special Issue Cyclophilins and Viruses)
Open AccessArticle Development of a Murine Model for Aerosolized Ebolavirus Infection Using a Panel of Recombinant Inbred Mice
Viruses 2012, 4(12), 3468-3493; doi:10.3390/v4123468
Received: 8 November 2012 / Revised: 23 November 2012 / Accepted: 30 November 2012 / Published: 3 December 2012
Cited by 9 | PDF Full-text (6949 KB) | HTML Full-text | XML Full-text
Abstract
Countering aerosolized filovirus infection is a major priority of biodefense research.  Aerosol models of filovirus infection have been developed in knock-out mice, guinea pigs and non-human primates; however, filovirus infection of immunocompetent mice by the aerosol route has not been reported.  A [...] Read more.
Countering aerosolized filovirus infection is a major priority of biodefense research.  Aerosol models of filovirus infection have been developed in knock-out mice, guinea pigs and non-human primates; however, filovirus infection of immunocompetent mice by the aerosol route has not been reported.  A murine model of aerosolized filovirus infection in mice should be useful for screening vaccine candidates and therapies.  In this study, various strains of wild-type and immunocompromised mice were exposed to aerosolized wild-type (WT) or mouse-adapted (MA) Ebola virus (EBOV).  Upon exposure to aerosolized WT-EBOV, BALB/c, C57BL/6 (B6), and DBA/2 (D2) mice were unaffected, but 100% of severe combined immunodeficiency (SCID) and 90% of signal transducers and activators of transcription (Stat1) knock-out (KO) mice became moribund between 7–9 days post-exposure (dpe).  Exposure to MA-EBOV caused 15% body weight loss in BALB/c, but all mice recovered.  In contrast, 10–30% lethality was observed in B6 and D2 mice exposed to aerosolized MA-EBOV, and 100% of SCID, Stat1 KO, interferon (IFN)-γ KO and Perforin KO mice became moribund between 7–14 dpe. In order to identify wild-type, inbred, mouse strains in which exposure to aerosolized MA-EBOV is uniformly lethal, 60 BXD (C57BL/6 crossed with DBA/2) recombinant inbred (RI) and advanced RI (ARI) mouse strains were exposed to aerosolized MA-EBOV, and monitored for disease severity. A complete spectrum of disease severity was observed. All BXD strains lost weight but many recovered. However, infection was uniformly lethal within 7 to 12 days post-exposure in five BXD strains.  Aerosol exposure of these five BXD strains to 10-fold less MA-EBOV resulted in lethality ranging from 0% in two strains to 90–100% lethality in two strains.  Analysis of post-mortem tissue from BXD strains that became moribund and were euthanized at the lower dose of MA-EBOV, showed liver damage in all mice as well as lung lesions in two of the three strains.  The two BXD strains that exhibited 90–100% mortality, even at a low dose of airborne MA-EBOV will be useful mouse models for testing vaccines and therapies. Additionally, since disease susceptibility is affected by complex genetic traits, a systems genetics approach was used to identify preliminary gene loci modulating disease severity among the panel BXD strains. Preliminary quantitative trait loci (QTLs) were identified that are likely to harbor genes involved in modulating differential susceptibility to Ebola infection. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessArticle Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies
Viruses 2012, 4(12), 3511-3530; doi:10.3390/v4123511
Received: 12 October 2012 / Revised: 10 November 2012 / Accepted: 20 November 2012 / Published: 6 December 2012
Cited by 13 | PDF Full-text (1221 KB) | HTML Full-text | XML Full-text
Abstract
The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate [...] Read more.
The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessArticle Molecular Adjuvant Ag85A Enhances Protection against Influenza A Virus in Mice Following DNA Vaccination
Viruses 2012, 4(12), 3606-3624; doi:10.3390/v4123606
Received: 14 October 2012 / Revised: 7 November 2012 / Accepted: 21 November 2012 / Published: 10 December 2012
Cited by 4 | PDF Full-text (583 KB) | HTML Full-text | XML Full-text
Abstract
A novel DNA vaccine vector encoding the Mycobacterium tuberculosis secreted antigen Ag85A fused with the influenza A virus (IAV) HA2 protein epitopes, pEGFP/Ag85A-sHA2 (pAg85A-sHA2), was designed to provide protection against influenza. The antigen encoded by the DNA vaccine vector was efficiently expressed [...] Read more.
A novel DNA vaccine vector encoding the Mycobacterium tuberculosis secreted antigen Ag85A fused with the influenza A virus (IAV) HA2 protein epitopes, pEGFP/Ag85A-sHA2 (pAg85A-sHA2), was designed to provide protection against influenza. The antigen encoded by the DNA vaccine vector was efficiently expressed in mammalian cells, as determined by reverse transcription polymerase chain reaction (RT-PCR) and fluorescence analyses. Mice were immunized with the vaccine vector by intramuscular injection before challenge with A/Puerto Rico/8/34 virus (PR8 virus). Sera and the splenocyte culture IFN-γ levels were significantly higher in immunized mice compared with the control mice. The novel vaccine group showed a high neutralization antibody titer in vitro. The novel vaccine vector also reduced the viral loads, increased the survival rates in mice after the PR8 virus challenge and reduced the alveolar inflammatory cell numbers. Sera IL-4 concentrations were significantly increased in mice immunized with the novel vaccine vector on Day 12 after challenge with the PR8 virus. These results demonstrated that short HA2 (sHA2) protein epitopes may provide protection against the PR8 virus and that Ag85A could strengthen the immune response to HA2 epitopes, thus, Ag85A may be developed as a new adjuvant for influenza vaccines. Full article
(This article belongs to the Section Antivirals & Vaccines)
Open AccessArticle Identification and Characterization of a Novel Alpaca Respiratory Coronavirus Most Closely Related to the Human Coronavirus 229E
Viruses 2012, 4(12), 3689-3700; doi:10.3390/v4123689
Received: 11 October 2012 / Revised: 13 November 2012 / Accepted: 23 November 2012 / Published: 12 December 2012
Cited by 7 | PDF Full-text (611 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In 2007, a novel coronavirus associated with an acute respiratory disease in alpacas (Alpaca Coronavirus, ACoV) was isolated. Full-length genomic sequencing of the ACoV demonstrated the genome to be consistent with other Alphacoronaviruses. A putative additional open-reading frame was identified between the [...] Read more.
In 2007, a novel coronavirus associated with an acute respiratory disease in alpacas (Alpaca Coronavirus, ACoV) was isolated. Full-length genomic sequencing of the ACoV demonstrated the genome to be consistent with other Alphacoronaviruses. A putative additional open-reading frame was identified between the nucleocapsid gene and 3'UTR. The ACoV was genetically most similar to the common human coronavirus (HCoV) 229E with 92.2% nucleotide identity over the entire genome. A comparison of spike gene sequences from ACoV and from HCoV-229E isolates recovered over a span of five decades showed the ACoV to be most similar to viruses isolated in the 1960’s to early 1980’s. The true origin of the ACoV is unknown, however a common ancestor between the ACoV and HCoV-229E appears to have existed prior to the 1960’s, suggesting virus transmission, either as a zoonosis or anthroponosis, has occurred between alpacas and humans. Full article
(This article belongs to the Special Issue Perspectives and Challenges in Coronavirus Research)
Open AccessArticle Diversity in Glycosaminoglycan Binding Amongst hMPV G Protein Lineages
Viruses 2012, 4(12), 3785-3803; doi:10.3390/v4123785
Received: 31 October 2012 / Revised: 10 December 2012 / Accepted: 10 December 2012 / Published: 14 December 2012
Cited by 5 | PDF Full-text (466 KB) | HTML Full-text | XML Full-text
Abstract
We have previously shown that hMPV G protein (B2 lineage) interacts with cellular glycosaminoglycans (GAGs). In this study we examined subtypes A1, A2 and B1 for this interaction. GAG-dependent infectivity of available hMPV strains was demonstrated using GAG-deficient cells and heparin competition. [...] Read more.
We have previously shown that hMPV G protein (B2 lineage) interacts with cellular glycosaminoglycans (GAGs). In this study we examined subtypes A1, A2 and B1 for this interaction. GAG-dependent infectivity of available hMPV strains was demonstrated using GAG-deficient cells and heparin competition. We expressed the G protein ectodomains from all strains and analysed these by heparin affinity chromatography. In contrast to the B2 lineage, neither the A2 or B1 G proteins bound to heparin. Sequence analysis of these strains indicated that although there was some homology with the B2 heparin-binding domains, there were less positively charged residues, providing a likely explanation for the lack of binding. Although sequence analysis did not demonstrate well defined positively charged domains in G protein of the A1 strain, this protein was able to bind heparin, albeit with a lower affinity than G protein of the B2 strain. These results indicate diversity in GAG interactions between G proteins of different lineages and suggest that the GAG-dependency of all strains may be mediated by interaction with an alternative surface protein, most probably the conserved fusion (F) protein. Analysis of both native and recombinant F protein confirmed that F protein binds heparin, supporting this conclusion. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)
Open AccessArticle First Report of Cowpea Mild Mottle Carlavirus on Yardlong Bean (Vigna unguiculata subsp. sesquipedalis) in Venezuela
Viruses 2012, 4(12), 3804-3811; doi:10.3390/v4123804
Received: 4 November 2012 / Revised: 6 December 2012 / Accepted: 11 December 2012 / Published: 14 December 2012
Cited by 4 | PDF Full-text (546 KB) | HTML Full-text | XML Full-text
Abstract
Yardlong bean (Vigna unguiculata subsp. sesquipedalis) plants with virus-like systemic mottling and leaf distortion were observed in both experimental and commercial fields in Aragua State, Venezuela. Symptomatic leaves were shown to contain carlavirus-like particles. RT-PCR analysis with carlavirus-specific primers was [...] Read more.
Yardlong bean (Vigna unguiculata subsp. sesquipedalis) plants with virus-like systemic mottling and leaf distortion were observed in both experimental and commercial fields in Aragua State, Venezuela. Symptomatic leaves were shown to contain carlavirus-like particles. RT-PCR analysis with carlavirus-specific primers was positive in all tested samples. Nucleotide sequences of the obtained amplicons showed 84%–74% similarity to corresponding sequences of Cowpea mild mottle virus (CPMMV) isolates deposited in the GenBank database. This is the first report of CPMMV in Venezuela and is thought to be the first report of CPMMV infecting yardlong bean. Full article
(This article belongs to the Section Viruses of Plants, Fungi and Protoza)

Review

Jump to: Research, Other

Open AccessReview Respiratory Syncytial Virus Persistence in Macrophages Alters the Profile of Cellular Gene Expression
Viruses 2012, 4(12), 3270-3280; doi:10.3390/v4123270
Received: 23 October 2012 / Revised: 14 November 2012 / Accepted: 15 November 2012 / Published: 22 November 2012
Cited by 6 | PDF Full-text (400 KB) | HTML Full-text | XML Full-text
Abstract
Viruses can persistently infect differentiated cells through regulation of expression of both their own genes and those of the host cell, thereby evading detection by the host’s immune system and achieving residence in a non-lytic state. Models in vitro with cell lines [...] Read more.
Viruses can persistently infect differentiated cells through regulation of expression of both their own genes and those of the host cell, thereby evading detection by the host’s immune system and achieving residence in a non-lytic state. Models in vitro with cell lines are useful tools in understanding the mechanisms associated with the establishment of viral persistence. In particular, a model to study respiratory syncytial virus (RSV) persistence in a murine macrophage-like cell line has been established. Compared to non-infected macrophages, macrophages persistently infected with RSV show altered expression both of genes coding for cytokines and trans-membrane proteins associated with antigen uptake and of genes related to cell survival. The biological changes associated with altered gene expression in macrophages as a consequence of persistent RSV infection are summarized. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)
Open AccessReview Host Genetic Variants in the Pathogenesis of Hepatitis C
Viruses 2012, 4(12), 3281-3302; doi:10.3390/v4123281
Received: 26 October 2012 / Revised: 17 November 2012 / Accepted: 17 November 2012 / Published: 22 November 2012
Cited by 15 | PDF Full-text (351 KB) | HTML Full-text | XML Full-text
Abstract
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment [...] Read more.
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview The Staphylococci Phages Family: An Overview
Viruses 2012, 4(12), 3316-3335; doi:10.3390/v4123316
Received: 1 November 2012 / Revised: 14 November 2012 / Accepted: 16 November 2012 / Published: 23 November 2012
Cited by 29 | PDF Full-text (392 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Due to their crucial role in pathogenesis and virulence, phages of Staphylococcus aureus have been extensively studied. Most of them encode and disseminate potent staphylococcal virulence factors. In addition, their movements contribute to the extraordinary versatility and adaptability of this prominent pathogen [...] Read more.
Due to their crucial role in pathogenesis and virulence, phages of Staphylococcus aureus have been extensively studied. Most of them encode and disseminate potent staphylococcal virulence factors. In addition, their movements contribute to the extraordinary versatility and adaptability of this prominent pathogen by improving genome plasticity. In addition to S. aureus, phages from coagulase-negative Staphylococci (CoNS) are gaining increasing interest. Some of these species, such as S. epidermidis, cause nosocomial infections and are therefore problematic for public health. This review provides an overview of the staphylococcal phages family extended to CoNS phages. At the morphological level, all these phages characterized so far belong to the Caudovirales order and are mainly temperate Siphoviridae. At the molecular level, comparative genomics revealed an extensive mosaicism, with genes organized into functional modules that are frequently exchanged between phages. Evolutionary relationships within this family, as well as with other families, have been highlighted. All these aspects are of crucial importance for our understanding of evolution and emergence of pathogens among bacterial species such as Staphylococci. Full article
(This article belongs to the Special Issue Recent Progress in Bacteriophage Research) Print Edition available
Open AccessReview Host Cell Factors in Filovirus Entry: Novel Players, New Insights
Viruses 2012, 4(12), 3336-3362; doi:10.3390/v4123336
Received: 23 October 2012 / Revised: 12 November 2012 / Accepted: 13 November 2012 / Published: 26 November 2012
Cited by 15 | PDF Full-text (605 KB) | HTML Full-text | XML Full-text
Abstract
Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed [...] Read more.
Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed important insights into the host cell molecules engaged by GP for cellular entry. The binding of GP to cellular lectins was found to concentrate virions onto susceptible cells and might contribute to the early and sustained infection of macrophages and dendritic cells, important viral targets. Tyrosine kinase receptors were shown to promote macropinocytic uptake of filoviruses into a subset of susceptible cells without binding to GP, while interactions between GP and human T cell Ig mucin 1 (TIM-1) might contribute to filovirus infection of mucosal epithelial cells. Moreover, GP engagement of the cholesterol transporter Niemann-Pick C1 was demonstrated to be essential for GP-mediated fusion of the viral envelope with a host cell membrane. Finally, mutagenic and structural analyses defined GP domains which interact with these host cell factors. Here, we will review the recent progress in elucidating the molecular interactions underlying filovirus entry and discuss their implications for our understanding of the viral cell tropism. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessReview Innate Immunity to H5N1 Influenza Viruses in Humans
Viruses 2012, 4(12), 3363-3388; doi:10.3390/v4123363
Received: 3 November 2012 / Revised: 19 November 2012 / Accepted: 21 November 2012 / Published: 26 November 2012
Cited by 17 | PDF Full-text (1998 KB) | HTML Full-text | XML Full-text
Abstract
Avian influenza virus infections in the human population are rare due to their inefficient direct human-to-human transmission. However, when humans are infected, a strong inflammatory response is usually induced, characterized by elevated levels of cytokines and chemokines in serum, believed to be [...] Read more.
Avian influenza virus infections in the human population are rare due to their inefficient direct human-to-human transmission. However, when humans are infected, a strong inflammatory response is usually induced, characterized by elevated levels of cytokines and chemokines in serum, believed to be important in the severe pathogenesis that develops in a high proportion of these patients. Extensive research has been performed to understand the molecular viral mechanisms involved in the H5N1 pathogenesis in humans, providing interesting insights about the virus-host interaction and the regulation of the innate immune response by these highly pathogenic viruses. In this review we summarize and discuss the most important findings in this field, focusing mainly on H5N1 virulence factors and their impact on the modulation of the innate immunity in humans. Full article
(This article belongs to the Special Issue H5N1 Influenza Virus)
Open AccessReview Prion Disease and the Innate Immune System
Viruses 2012, 4(12), 3389-3419; doi:10.3390/v4123389
Received: 6 October 2012 / Revised: 14 November 2012 / Accepted: 22 November 2012 / Published: 28 November 2012
Cited by 12 | PDF Full-text (1439 KB) | HTML Full-text | XML Full-text
Abstract
Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered [...] Read more.
Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis. Full article
(This article belongs to the Special Issue Recent Developments in the Prion Field)
Figures

Open AccessReview Epstein-Barr Virus (EBV)-associated Gastric Carcinoma
Viruses 2012, 4(12), 3420-3439; doi:10.3390/v4123420
Received: 22 October 2012 / Revised: 22 November 2012 / Accepted: 26 November 2012 / Published: 29 November 2012
Cited by 38 | PDF Full-text (1191 KB) | HTML Full-text | XML Full-text
Abstract
The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute [...] Read more.
The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis.  Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented.  Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed. Full article
(This article belongs to the Special Issue Recent Progress in EBV Research)
Open AccessReview Involvement of Autophagy in Coronavirus Replication
Viruses 2012, 4(12), 3440-3451; doi:10.3390/v4123440
Received: 27 September 2012 / Revised: 26 November 2012 / Accepted: 27 November 2012 / Published: 30 November 2012
Cited by 13 | PDF Full-text (600 KB) | HTML Full-text | XML Full-text
Abstract
Coronaviruses are single stranded, positive sense RNA viruses, which induce the rearrangement of cellular membranes upon infection of a host cell. This provides the virus with a platform for the assembly of viral replication complexes, improving efficiency of RNA synthesis. The membranes [...] Read more.
Coronaviruses are single stranded, positive sense RNA viruses, which induce the rearrangement of cellular membranes upon infection of a host cell. This provides the virus with a platform for the assembly of viral replication complexes, improving efficiency of RNA synthesis. The membranes observed in coronavirus infected cells include double membrane vesicles. By nature of their double membrane, these vesicles resemble cellular autophagosomes, generated during the cellular autophagy pathway. In addition, coronavirus infection has been demonstrated to induce autophagy. Here we review current knowledge of coronavirus induced membrane rearrangements and the involvement of autophagy or autophagy protein microtubule associated protein 1B light chain 3 (LC3) in coronavirus replication. Full article
(This article belongs to the Special Issue Perspectives and Challenges in Coronavirus Research)
Open AccessReview Epidemiology, Molecular Epidemiology and Evolution of Bovine Respiratory Syncytial Virus
Viruses 2012, 4(12), 3452-3467; doi:10.3390/v4123452
Received: 29 October 2012 / Revised: 22 November 2012 / Accepted: 23 November 2012 / Published: 30 November 2012
Cited by 4 | PDF Full-text (365 KB) | HTML Full-text | XML Full-text
Abstract
The bovine respiratory syncytial virus (BRSV) is an enveloped, negative sense, single-stranded RNA virus belonging to the pneumovirus genus within the family Paramyxoviridae. BRSV has been recognized as a major cause of respiratory disease in young calves since the early 1970s. The [...] Read more.
The bovine respiratory syncytial virus (BRSV) is an enveloped, negative sense, single-stranded RNA virus belonging to the pneumovirus genus within the family Paramyxoviridae. BRSV has been recognized as a major cause of respiratory disease in young calves since the early 1970s. The analysis of BRSV infection was originally hampered by its characteristic lability and poor growth in vitro. However, the advent of numerous immunological and molecular methods has facilitated the study of BRSV enormously. The knowledge gained from these studies has also provided the opportunity to develop safe, stable, attenuated virus vaccine candidates. Nonetheless, many aspects of the epidemiology, molecular epidemiology and evolution of the virus are still not fully understood. The natural course of infection is rather complex and further complicates diagnosis, treatment and the implementation of preventive measures aimed to control the disease. Therefore, understanding the mechanisms by which BRSV is able to establish infection is needed to prevent viral and disease spread. This review discusses important information regarding the epidemiology and molecular epidemiology of BRSV worldwide, and it highlights the importance of viral evolution in virus transmission. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)
Open AccessReview The Pneumonia Virus of Mice (PVM) Model of Acute Respiratory Infection
Viruses 2012, 4(12), 3494-3510; doi:10.3390/v4123494
Received: 7 November 2012 / Revised: 28 November 2012 / Accepted: 28 November 2012 / Published: 5 December 2012
Cited by 14 | PDF Full-text (802 KB) | HTML Full-text | XML Full-text
Abstract
Pneumonia Virus of Mice (PVM) is related to the human and bovine respiratory syncytial virus (RSV) pathogens, and has been used to study respiratory virus replication and the ensuing inflammatory response as a component of a natural host—pathogen relationship. As such, PVM [...] Read more.
Pneumonia Virus of Mice (PVM) is related to the human and bovine respiratory syncytial virus (RSV) pathogens, and has been used to study respiratory virus replication and the ensuing inflammatory response as a component of a natural host—pathogen relationship. As such, PVM infection in mice reproduces many of the clinical and pathologic features of the more severe forms of RSV infection in human infants. Here we review some of the most recent findings on the basic biology of PVM infection and its use as a model of disease, most notably for explorations of virus infection and allergic airways disease, for vaccine evaluation, and for the development of immunomodulatory strategies for acute respiratory virus infection. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)
Open AccessReview Pathogenesis of Hepatitis C During Pregnancy and Childhood
Viruses 2012, 4(12), 3531-3550; doi:10.3390/v4123531
Received: 2 November 2012 / Revised: 18 November 2012 / Accepted: 28 November 2012 / Published: 6 December 2012
Cited by 16 | PDF Full-text (601 KB) | HTML Full-text | XML Full-text
Abstract
The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading [...] Read more.
The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading cause of pediatric HCV infection, takes place at a rate of <10%. Factors that increase the risk of MTCT include high maternal HCV viral load and coinfection with HIV-1 but, intriguingly, not breastfeeding and mode of delivery. Pharmacological prevention of MTCT is not possible at the present time because both pegylated interferon alfa and ribavirin are contraindicated for use in pregnancy and during the neonatal period. However, this may change with the recent introduction of direct acting antiviral agents. This review summarizes what is currently known about HCV infection during pregnancy and childhood. Particular emphasis is placed on how pregnancy-associated immune modulation may influence the progression of HCV disease and impact MTCT, and on the differential evolution of perinatally acquired HCV infection in children. Taken together, these developments provide insights into the pathogenesis of hepatitis C and may inform strategies to prevent the transmission of HCV from mother to child. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview Human Metapneumovirus Antagonism of Innate Immune Responses
Viruses 2012, 4(12), 3551-3571; doi:10.3390/v4123551
Received: 1 November 2012 / Revised: 20 November 2012 / Accepted: 30 November 2012 / Published: 7 December 2012
Cited by 9 | PDF Full-text (920 KB) | HTML Full-text | XML Full-text
Abstract
Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the Paramyxoviridae family, which includes several major human and animal pathogens. Epidemiological studies indicate that hMPV is a significant human respiratory pathogen with worldwide distribution. It is associated with respiratory illnesses [...] Read more.
Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the Paramyxoviridae family, which includes several major human and animal pathogens. Epidemiological studies indicate that hMPV is a significant human respiratory pathogen with worldwide distribution. It is associated with respiratory illnesses in children, adults, and immunocompromised patients, ranging from upper respiratory tract infections to severe bronchiolitis and pneumonia. Interferon (IFN) represents a major line of defense against virus infection, and in response, viruses have evolved countermeasures to inhibit IFN production as well as IFN signaling. Although the strategies of IFN evasion are similar, the specific mechanisms by which paramyxoviruses inhibit IFN responses are quite diverse. In this review, we will present an overview of the strategies that hMPV uses to subvert cellular signaling in airway epithelial cells, the major target of infection, as well as in primary immune cells. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)
Open AccessReview Large Animal Models for Foamy Virus Vector Gene Therapy
Viruses 2012, 4(12), 3572-3588; doi:10.3390/v4123572
Received: 15 October 2012 / Revised: 19 November 2012 / Accepted: 28 November 2012 / Published: 7 December 2012
Cited by 7 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
Foamy virus (FV) vectors have shown great promise for hematopoietic stem cell (HSC) gene therapy. Their ability to efficiently deliver transgenes to multi-lineage long-term repopulating cells in large animal models suggests they will be effective for several human hematopoietic diseases. Here, we [...] Read more.
Foamy virus (FV) vectors have shown great promise for hematopoietic stem cell (HSC) gene therapy. Their ability to efficiently deliver transgenes to multi-lineage long-term repopulating cells in large animal models suggests they will be effective for several human hematopoietic diseases. Here, we review FV vector studies in large animal models, including the use of FV vectors with the mutant O6-methylguanine-DNA methyltransferase, MGMTP140K to increase the number of genetically modified cells after transplantation. In these studies, FV vectors have mediated efficient gene transfer to polyclonal repopulating cells using short ex vivo transduction protocols designed to minimize the negative effects of ex vivo culture on stem cell engraftment. In this regard, FV vectors appear superior to gammaretroviral vectors, which require longer ex vivo culture to effect efficient transduction. FV vectors have also compared favorably with lentiviral vectors when directly compared in the dog model. FV vectors have corrected leukocyte adhesion deficiency and pyruvate kinase deficiency in the dog large animal model. FV vectors also appear safer than gammaretroviral vectors based on a reduced frequency of integrants near promoters and also near proto-oncogenes in canine repopulating cells. Together, these studies suggest that FV vectors should be highly effective for several human hematopoietic diseases, including those that will require relatively high percentages of gene-modified cells to achieve clinical benefit. Full article
(This article belongs to the Special Issue Recent Progress in Foamy Virus (FV) Research)
Open AccessReview Development of Live-Attenuated Influenza Vaccines against Outbreaks of H5N1 Influenza
Viruses 2012, 4(12), 3589-3605; doi:10.3390/v4123589
Received: 2 October 2012 / Revised: 14 November 2012 / Accepted: 22 November 2012 / Published: 10 December 2012
Cited by 2 | PDF Full-text (272 KB) | HTML Full-text | XML Full-text
Abstract
Several global outbreaks of highly pathogenic avian influenza (HPAI) H5N1 virus have increased the urgency of developing effective and safe vaccines against H5N1. Compared with H5N1 inactivated vaccines used widely, H5N1 live-attenuated influenza vaccines (LAIVs) have advantages in vaccine efficacy, dose-saving formula, [...] Read more.
Several global outbreaks of highly pathogenic avian influenza (HPAI) H5N1 virus have increased the urgency of developing effective and safe vaccines against H5N1. Compared with H5N1 inactivated vaccines used widely, H5N1 live-attenuated influenza vaccines (LAIVs) have advantages in vaccine efficacy, dose-saving formula, long-lasting effect, ease of administration and some cross-protective immunity. Furthermore, H5N1 LAIVs induce both humoral and cellular immune responses, especially including improved IgA production at the mucosa. The current trend of H5N1 LAIVs development is toward cold-adapted, temperature-sensitive or replication-defective vaccines, and moreover, H5N1 LAIVs plus mucosal adjuvants are promising candidates. This review provides an update on the advantages and development of H5N1 live-attenuated influenza vaccines. Full article
(This article belongs to the Special Issue H5N1 Influenza Virus)
Open AccessReview A Systems Biology Starter Kit for Arenaviruses
Viruses 2012, 4(12), 3625-3646; doi:10.3390/v4123625
Received: 29 October 2012 / Revised: 28 November 2012 / Accepted: 5 December 2012 / Published: 11 December 2012
PDF Full-text (802 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Systems biology approaches in virology aim to integrate viral and host biological networks, and thus model the infection process. The growing availability of high-throughput “-omics” techniques and datasets, as well as the ever-increasing sophistication of in silico modeling tools, has resulted in [...] Read more.
Systems biology approaches in virology aim to integrate viral and host biological networks, and thus model the infection process. The growing availability of high-throughput “-omics” techniques and datasets, as well as the ever-increasing sophistication of in silico modeling tools, has resulted in a corresponding rise in the complexity of the analyses that can be performed. The present study seeks to review and organize published evidence regarding virus-host interactions for the arenaviruses, from alterations in the host proteome during infection, to reported protein-protein interactions. In this way, we hope to provide an overview of the interplay between arenaviruses and the host cell, and lay the foundations for complementing current arenavirus research with a systems-level approach. Full article
(This article belongs to the Special Issue Arenaviruses)
Figures

Open AccessReview Endocytic Pathways Involved in Filovirus Entry: Advances, Implications and Future Directions
Viruses 2012, 4(12), 3647-3664; doi:10.3390/v4123647
Received: 7 November 2012 / Revised: 28 November 2012 / Accepted: 30 November 2012 / Published: 11 December 2012
Cited by 5 | PDF Full-text (430 KB) | HTML Full-text | XML Full-text
Abstract
Detailed knowledge of the host-virus interactions that accompany filovirus entry into cells is expected to identify determinants of viral virulence and host range, and to yield targets for the development of antiviral therapeutics. While it is generally agreed that filovirus entry into [...] Read more.
Detailed knowledge of the host-virus interactions that accompany filovirus entry into cells is expected to identify determinants of viral virulence and host range, and to yield targets for the development of antiviral therapeutics. While it is generally agreed that filovirus entry into the host cytoplasm requires viral internalization into acidic endosomal compartments and proteolytic cleavage of the envelope glycoprotein by endo/lysosomal cysteine proteases, our understanding of the specific endocytic pathways co-opted by filoviruses remains limited. This review addresses the current knowledge on cellular endocytic pathways implicated in filovirus entry, highlights the consensus as well as controversies, and discusses important remaining questions. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessReview Biological Invasions of Geminiviruses: Case Study of TYLCV and Bemisia tabaci in Reunion Island
Viruses 2012, 4(12), 3665-3688; doi:10.3390/v4123665
Received: 5 November 2012 / Revised: 6 December 2012 / Accepted: 6 December 2012 / Published: 12 December 2012
Cited by 6 | PDF Full-text (664 KB) | HTML Full-text | XML Full-text
Abstract
In the last 20 years, molecular ecology approaches have proven to be extremely useful to identify and assess factors associated with viral emerging diseases, particularly in economically and socially important tropical crops such as maize (maize streak disease) and cassava (cassava mosaic [...] Read more.
In the last 20 years, molecular ecology approaches have proven to be extremely useful to identify and assess factors associated with viral emerging diseases, particularly in economically and socially important tropical crops such as maize (maize streak disease) and cassava (cassava mosaic disease). Molecular ecology approaches were applied in Reunion Island to analyze the epidemic of tomato yellow leaf curl disease, which has been affecting the island since the end of the 1990s. Before the invasive biotype B (currently known as Middle East-Asia Minor 1 cryptic species) of Bemisia tabaci spread across the world, Reunion Island (South West Indian Ocean) only hosted an indigenous biotype of B. tabaci, Ms (currently known as Indian Ocean cryptic species). Wild hybrids between invasive and indigenous species were subsequently characterized over multiple generations. Endosymbiont analysis of the hybrid population indicated that matings were non-random. Similarly, while no indigenous begomoviruses have ever been reported on Reunion Island, the two main strains of one of the most damaging and emerging plant viruses in the world, the Mild and Israel strains of the Tomato yellow leaf curl virus (TYLCV-Mld and TYLCV-IL), were introduced in 1997 and 2004 respectively. While these introductions extensively modified the agricultural landscape of Reunion Island, they also provided an invaluable opportunity to study the ecological and genetic mechanisms involved in biological invasion and competition. Full article
(This article belongs to the Special Issue Plant Viruses)
Open AccessReview Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation
Viruses 2012, 4(12), 3701-3730; doi:10.3390/v4123701
Received: 31 October 2012 / Revised: 6 December 2012 / Accepted: 7 December 2012 / Published: 13 December 2012
Cited by 30 | PDF Full-text (489 KB) | HTML Full-text | XML Full-text
Abstract
Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if [...] Read more.
Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity. Full article
(This article belongs to the Special Issue Recent Progress in EBV Research)
Open AccessReview Neonatal Calf Infection with Respiratory Syncytial Virus: Drawing Parallels to the Disease in Human Infants
Viruses 2012, 4(12), 3731-3753; doi:10.3390/v4123731
Received: 1 November 2012 / Revised: 29 November 2012 / Accepted: 7 December 2012 / Published: 13 December 2012
Cited by 5 | PDF Full-text (399 KB) | HTML Full-text | XML Full-text
Abstract
Respiratory syncytial virus (RSV) is the most common viral cause of childhood acute lower respiratory tract infections. It is estimated that RSV infections result in more than 100,000 deaths annually worldwide. Bovine RSV is a cause of enzootic pneumonia in young dairy [...] Read more.
Respiratory syncytial virus (RSV) is the most common viral cause of childhood acute lower respiratory tract infections. It is estimated that RSV infections result in more than 100,000 deaths annually worldwide. Bovine RSV is a cause of enzootic pneumonia in young dairy calves and summer pneumonia in nursing beef calves. Furthermore, bovine RSV plays a significant role in bovine respiratory disease complex, the most prevalent cause of morbidity and mortality among feedlot cattle. Infection of calves with bovine RSV shares features in common with RSV infection in children, such as an age-dependent susceptibility. In addition, comparable microscopic lesions consisting of bronchiolar neutrophilic infiltrates, epithelial cell necrosis, and syncytial cell formation are observed. Further, our studies have shown an upregulation of pro-inflammatory mediators in RSV-infected calves, including IL-12p40 and CXCL8 (IL-8). This finding is consistent with increased levels of IL-8 observed in children with RSV bronchiolitis. Since rodents lack IL-8, neonatal calves can be useful for studies of IL-8 regulation in response to RSV infection. We have recently found that vitamin D in milk replacer diets can be manipulated to produce calves differing in circulating 25-hydroxyvitamin D3. The results to date indicate that although the vitamin D intracrine pathway is activated during RSV infection, pro-inflammatory mediators frequently inhibited by the vitamin D intacrine pathway in vitro are, in fact, upregulated or unaffected in lungs of infected calves. This review will summarize available data that provide parallels between bovine RSV infection in neonatal calves and human RSV in infants. Full article
(This article belongs to the Special Issue Pneumoviruses and Metapneumoviruses)
Open AccessReview Use of the Syrian Hamster as a New Model of Ebola Virus Disease and Other Viral Hemorrhagic Fevers
Viruses 2012, 4(12), 3754-3784; doi:10.3390/v4123754
Received: 14 November 2012 / Revised: 10 December 2012 / Accepted: 12 December 2012 / Published: 14 December 2012
Cited by 18 | PDF Full-text (1326 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Historically, mice and guinea pigs have been the rodent models of choice for therapeutic and prophylactic countermeasure testing against Ebola virus disease (EVD). Recently, hamsters have emerged as a novel animal model for the in vivo study of EVD. In this review, [...] Read more.
Historically, mice and guinea pigs have been the rodent models of choice for therapeutic and prophylactic countermeasure testing against Ebola virus disease (EVD). Recently, hamsters have emerged as a novel animal model for the in vivo study of EVD. In this review, we discuss the history of the hamster as a research laboratory animal, as well as current benefits and challenges of this model. Availability of immunological reagents is addressed. Salient features of EVD in hamsters, including relevant pathology and coagulation parameters, are compared directly with the mouse, guinea pig and nonhuman primate models. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available
Open AccessReview Immune Responses to West Nile Virus Infection in the Central Nervous System
Viruses 2012, 4(12), 3812-3830; doi:10.3390/v4123812
Received: 20 November 2012 / Revised: 7 December 2012 / Accepted: 10 December 2012 / Published: 17 December 2012
Cited by 20 | PDF Full-text (532 KB) | HTML Full-text | XML Full-text
Abstract
West Nile virus (WNV) continues to cause outbreaks of severe neuroinvasive disease in humans and other vertebrate animals in the United States, Europe, and other regions of the world. This review discusses our understanding of the interactions between virus and host that [...] Read more.
West Nile virus (WNV) continues to cause outbreaks of severe neuroinvasive disease in humans and other vertebrate animals in the United States, Europe, and other regions of the world. This review discusses our understanding of the interactions between virus and host that occur in the central nervous system (CNS), the outcome of which can be protection, viral pathogenesis, or immunopathogenesis. We will focus on defining the current state of knowledge of WNV entry, tropism, and host immune response in the CNS, all of which affect the balance between injury and successful clearance. Full article
(This article belongs to the Special Issue Viral Infections of the CNS)
Open AccessReview Modulation of Apoptotic Pathways by Human Papillomaviruses (HPV): Mechanisms and Implications for Therapy
Viruses 2012, 4(12), 3831-3850; doi:10.3390/v4123831
Received: 16 November 2012 / Revised: 12 December 2012 / Accepted: 14 December 2012 / Published: 18 December 2012
Cited by 15 | PDF Full-text (486 KB) | HTML Full-text | XML Full-text
Abstract
The ability of the host to trigger apoptosis in infected cells is perhaps the most powerful tool by which viruses can be cleared from the host organism. To avoid elimination by this mechanism, human papillomaviruses (HPV) have developed several mechanisms that enable [...] Read more.
The ability of the host to trigger apoptosis in infected cells is perhaps the most powerful tool by which viruses can be cleared from the host organism. To avoid elimination by this mechanism, human papillomaviruses (HPV) have developed several mechanisms that enable the cells they infect to elude both extrinsic and intrinsic apoptosis. In this manuscript, we review the current literature regarding how HPV-infected cells avoid apoptosis and the molecular mechanisms involved in these events. In particular, we will discuss the modifications in intrinsic and extrinsic apoptotic pathways caused by proteins encoded by HPV early genes. Many of the current efforts regarding anti-cancer drug development are focused on directing tumor cells to undergo apoptosis. However, the ability of HPV-infected cells to resist apoptotic signals renders such therapies ineffective. Possible mechanisms for overcoming the resistance of HPV-infected tumor cells to anticancer drugs will be discussed. Full article
Open AccessReview The Role of Human Papillomavirus in Human Immunodeficiency Virus Acquisition in Men who Have Sex with Men: A Review of the Literature
Viruses 2012, 4(12), 3851-3858; doi:10.3390/v4123851
Received: 22 November 2012 / Revised: 14 December 2012 / Accepted: 17 December 2012 / Published: 18 December 2012
Cited by 11 | PDF Full-text (204 KB) | HTML Full-text | XML Full-text
Abstract
Human Papillomavirus (HPV) infection is the most common sexually transmitted infection (STI) worldwide. Incidence rates of HPV infection among human immunodeficiency virus (HIV)-infected individuals are well documented and are several-fold higher than among HIV-uninfected individuals. Few studies have demonstrated an increased risk [...] Read more.
Human Papillomavirus (HPV) infection is the most common sexually transmitted infection (STI) worldwide. Incidence rates of HPV infection among human immunodeficiency virus (HIV)-infected individuals are well documented and are several-fold higher than among HIV-uninfected individuals. Few studies have demonstrated an increased risk for acquiring HIV infection in those with HPV infection, and this risk seems to be higher when HPV strains are of high-risk oncogenic potential. The estimated prevalence of high-risk oncogenic HPV infection is highest in men who have sex with men (MSM), a particularly vulnerable group with high prevalence rates of HIV infection and other STIs. In this paper, we provide a comprehensive review of the available literature on the role of HPV infection in HIV acquisition. Our review includes data from cross-sectional and longitudinal studies. Full article
Open AccessReview Escape from Human Immunodeficiency Virus Type 1 (HIV-1) Entry Inhibitors
Viruses 2012, 4(12), 3859-3911; doi:10.3390/v4123859
Received: 6 November 2012 / Revised: 8 December 2012 / Accepted: 12 December 2012 / Published: 19 December 2012
Cited by 11 | PDF Full-text (806 KB) | HTML Full-text | XML Full-text
Abstract
The human immunodeficiency virus (HIV) enters cells through a series of molecular interactions between the HIV envelope protein and cellular receptors, thus providing many opportunities to block infection. Entry inhibitors are currently being used in the clinic, and many more are under [...] Read more.
The human immunodeficiency virus (HIV) enters cells through a series of molecular interactions between the HIV envelope protein and cellular receptors, thus providing many opportunities to block infection. Entry inhibitors are currently being used in the clinic, and many more are under development. Unfortunately, as is the case for other classes of antiretroviral drugs that target later steps in the viral life cycle, HIV can become resistant to entry inhibitors. In contrast to inhibitors that block viral enzymes in intracellular compartments, entry inhibitors interfere with the function of the highly variable envelope glycoprotein as it continuously adapts to changing immune pressure and available target cells in the extracellular environment. Consequently, pathways and mechanisms of resistance for entry inhibitors are varied and often involve mutations across the envelope gene. This review provides a broad overview of entry inhibitor resistance mechanisms that inform our understanding of HIV entry and the design of new inhibitors and vaccines. Full article
(This article belongs to the Special Issue Viral Entry Inhibitors)
Open AccessReview Hepatitis C Virus in American Indian/Alaskan Native and Aboriginal Peoples of North America
Viruses 2012, 4(12), 3912-3931; doi:10.3390/v4123912
Received: 24 October 2012 / Revised: 3 December 2012 / Accepted: 5 December 2012 / Published: 19 December 2012
Cited by 7 | PDF Full-text (218 KB) | HTML Full-text | XML Full-text
Abstract
Liver diseases, such as hepatitis C virus (HCV), are “broken spirit” diseases. The prevalence of HCV infection for American Indian/Alaskan Native (AI/AN) in the United States and Canadian Aboriginals varies; nonetheless, incidence rates of newly diagnosed HCV infection are typically higher relative [...] Read more.
Liver diseases, such as hepatitis C virus (HCV), are “broken spirit” diseases. The prevalence of HCV infection for American Indian/Alaskan Native (AI/AN) in the United States and Canadian Aboriginals varies; nonetheless, incidence rates of newly diagnosed HCV infection are typically higher relative to non-indigenous people. For AI/AN and Aboriginal peoples risk factors for the diagnosis of HCV can reflect that of the general population: predominately male, a history of injection drug use, in midlife years, with a connection with urban centers. However, the face of the indigenous HCV infected individual is becoming increasingly female and younger compared to non-indigenous counterparts. Epidemiology studies indicate that more effective clearance of acute HCV infection can occur for select Aboriginal populations, a phenomenon which may be linked to unique immune characteristics. For individuals progressing to chronic HCV infection treatment outcomes are comparable to other racial cohorts. Disease progression, however, is propelled by elevated rates of co-morbidities including type 2 diabetes and alcohol use, along with human immunodeficiency virus (HIV) co-infection relative to non-indigenous patients. Historical and personal trauma has a major role in the participation of high risk behaviors and associated diseases. Although emerging treatments provide hope, combating HCV related morbidity and mortality will require interventions that address the etiology of broken spirit diseases. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
Open AccessReview The Impact of Regulations, Safety Considerations and Physical Limitations on Research Progress at Maximum Biocontainment
Viruses 2012, 4(12), 3932-3951; doi:10.3390/v4123932
Received: 22 November 2012 / Revised: 14 December 2012 / Accepted: 14 December 2012 / Published: 19 December 2012
Cited by 6 | PDF Full-text (466 KB) | HTML Full-text | XML Full-text
Abstract
We describe herein, limitations on research at biosafety level 4 (BSL-4) containment laboratories, with regard to biosecurity regulations, safety considerations, research space limitations, and physical constraints in executing experimental procedures. These limitations can severely impact the number of collaborations and size of [...] Read more.
We describe herein, limitations on research at biosafety level 4 (BSL-4) containment laboratories, with regard to biosecurity regulations, safety considerations, research space limitations, and physical constraints in executing experimental procedures. These limitations can severely impact the number of collaborations and size of research projects investigating microbial pathogens of biodefense concern. Acquisition, use, storage, and transfer of biological select agents and toxins (BSAT) are highly regulated due to their potential to pose a severe threat to public health and safety. All federal, state, city, and local regulations must be followed to obtain and maintain registration for the institution to conduct research involving BSAT. These include initial screening and continuous monitoring of personnel, controlled access to containment laboratories, accurate and current BSAT inventory records. Safety considerations are paramount in BSL-4 containment laboratories while considering the types of research tools, workflow and time required for conducting both in vivo and in vitro experiments in limited space. Required use of a positive-pressure encapsulating suit imposes tremendous physical limitations on the researcher. Successful mitigation of these constraints requires additional time, effort, good communication, and creative solutions. Test and evaluation of novel vaccines and therapeutics conducted under good laboratory practice (GLP) conditions for FDA approval are prioritized and frequently share the same physical space with important ongoing basic research studies. The possibilities and limitations of biomedical research involving microbial pathogens of biodefense concern in BSL-4 containment laboratories are explored in this review. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012) Print Edition available

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Open AccessCorrection San Martín, C., Correction: Latest Insights on Adenovirus Structure and Assembly. Viruses 2012, 4, 847-877.
Viruses 2012, 4(12), 3952; doi:10.3390/v4123952
Received: 19 December 2012 / Accepted: 19 December 2012 / Published: 19 December 2012
PDF Full-text (16 KB) | HTML Full-text | XML Full-text
Abstract
It has come to my attention that my article "Latest Insights on Adenovirus Structure and Assembly" (Viruses 2012, 4, 847-877) [1] contains an inaccurate statement. On page 864, the caption for Figure 7 reads: "There are four potential cleavage sites [...] Read more.
It has come to my attention that my article "Latest Insights on Adenovirus Structure and Assembly" (Viruses 2012, 4, 847-877) [1] contains an inaccurate statement. On page 864, the caption for Figure 7 reads: "There are four potential cleavage sites in pTP but they have not been experimentally verified". However, three of these sites have been experimentally confirmed in vitro using recombinant AVP and pTP, as described in Webster A, Leith I.R., Hay R.T.: Activation of adenovirus-coded protease and processing of preterminal protein. J. Virol. 1994, 68, 7292-7300 [2]. [...] Full article

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