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Viruses, Volume 2, Issue 10 (October 2010), Pages 2154-2403

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Editorial

Jump to: Research, Review, Other

Open AccessEditorial Towards Viral Genome Annotation Standards, Report from the 2010 NCBI Annotation Workshop
Viruses 2010, 2(10), 2258-2268; doi:10.3390/v2102258
Received: 26 August 2010 / Revised: 18 September 2010 / Accepted: 20 September 2010 / Published: 13 October 2010
Cited by 14 | PDF Full-text (84 KB)
Abstract
Improvements in DNA sequencing technologies portend a new era in virology and could possibly lead to a giant leap in our understanding of viral evolution and ecology. Yet, as viral genome sequences begin to fill the world’s biological databases, it is critically important
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Improvements in DNA sequencing technologies portend a new era in virology and could possibly lead to a giant leap in our understanding of viral evolution and ecology. Yet, as viral genome sequences begin to fill the world’s biological databases, it is critically important to recognize that the scientific promise of this era is dependent on consistent and comprehensive genome annotation. With this in mind, the NCBI Genome Annotation Workshop recently hosted a study group tasked with developing sequence, function, and metadata annotation standards for viral genomes. This report describes the issues involved in viral genome annotation and reviews policy recommendations presented at the NCBI Annotation Workshop. Full article
(This article belongs to the Special Issue Viral Genomics and Bioinformatics)

Research

Jump to: Editorial, Review, Other

Open AccessArticle Neuraminidase Inhibitor Susceptibility Testing in Human Influenza Viruses: A Laboratory Surveillance Perspective
Viruses 2010, 2(10), 2269-2289; doi:10.3390/v2102269
Received: 30 August 2010 / Revised: 5 October 2010 / Accepted: 7 October 2010 / Published: 13 October 2010
Cited by 43 | PDF Full-text (419 KB) | Correction | Supplementary Files
Abstract
Neuraminidase inhibitors (NAIs) are vital in managing seasonal and pandemic influenza infections. NAI susceptibilities of virus isolates (n = 5540) collected during the 2008–2009 influenza season were assessed in the chemiluminescent neuraminidase inhibition (NI) assay. Box-and-whisker plot analyses of log-transformed IC50s
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Neuraminidase inhibitors (NAIs) are vital in managing seasonal and pandemic influenza infections. NAI susceptibilities of virus isolates (n = 5540) collected during the 2008–2009 influenza season were assessed in the chemiluminescent neuraminidase inhibition (NI) assay. Box-and-whisker plot analyses of log-transformed IC50s were performed for each virus type/subtype and NAI to identify outliers which were characterized based on a statistical cutoff of IC50 >3 interquartile ranges (IQR) from the 75th percentile. Among 1533 seasonal H1N1 viruses tested, 1431 (93.3%) were outliers for oseltamivir; they all harbored the H275Y mutation in the neuraminidase (NA) and were reported as oseltamivir-resistant. Only 15 (0.7%) of pandemic 2009 H1N1 viruses tested (n = 2259) were resistant to oseltamivir. All influenza A(H3N2) (n = 834) and B (n = 914) viruses were sensitive to oseltamivir, except for one A(H3N2) and one B virus, with D151V and D197E (D198E in N2 numbering) mutations in the NA, respectively. All viruses tested were sensitive to zanamivir, except for six seasonal A(H1N1) and several A(H3N2) outliers (n = 22) which exhibited cell culture induced mutations at residue D151 of the NA. A subset of viruses (n = 1058) tested for peramivir were sensitive to the drug, with exception of H275Y variants that exhibited reduced susceptibility to this NAI. This study summarizes baseline susceptibility patterns of seasonal and pandemic influenza viruses, and seeks to contribute towards criteria for defining NAI resistance. Full article
(This article belongs to the Special Issue Antivirals Against Influenza)
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Review

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Open AccessReview Antiviral Properties of ISG15
Viruses 2010, 2(10), 2154-2168; doi:10.3390/v2102154
Received: 2 August 2010 / Revised: 8 September 2010 / Accepted: 15 September 2010 / Published: 28 September 2010
Cited by 19 | PDF Full-text (198 KB)
Abstract
The type I interferon system plays a critical role in limiting the spread of viral infection. Viruses induce the production of interferon (IFN), which after binding to the IFN-α/β receptor (IFNAR), and triggering of the JAK/STAT signaling cascade, results in the induction of
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The type I interferon system plays a critical role in limiting the spread of viral infection. Viruses induce the production of interferon (IFN), which after binding to the IFN-α/β receptor (IFNAR), and triggering of the JAK/STAT signaling cascade, results in the induction of interferon-stimulated genes (ISGs). These ISGs function to inhibit viral replication and to regulate the host immune response. Among these ISGs, the ubiquitin-like molecule, ISG15, is one of the most strongly induced proteins. Similar to ubiquitin, through an IFN induced conjugation cascade, ISG15 is covalently linked to a variety of cellular proteins, suggesting regulation of different cellular processes. Studies performed over the past several years have shown that ISG15 plays a central role in the host’s antiviral response against many viruses. Mice lacking ISG15 display increased susceptibility to multiple viruses. Furthermore, several viruses have developed immune evasion strategies that directly target the ISG15 pathway. Work is now underway to determine the mechanism by which ISG15 functions as an antiviral molecule, such that therapies targeting this pathway can be developed in the future. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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Open AccessReview Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B
Viruses 2010, 2(10), 2169-2195; doi:10.3390/v2102169
Received: 29 July 2010 / Revised: 6 September 2010 / Accepted: 6 September 2010 / Published: 28 September 2010
Cited by 48 | PDF Full-text (640 KB)
Abstract
More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far
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More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far not everyone benefits from treatment. Recently, progress has been made in the development of specifically targeted antiviral therapy for HCV (STAT-C). A major target for such direct acting antivirals (DAAs) is the HCV RNA-dependent RNA polymerase or non-structural protein 5B (NS5B), which is essential for viral replication. This review will examine the current state of development of inhibitors targeting the polymerase and issues such as the emergence of antiviral resistance during treatment, as well as strategies to address this problem. Full article
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
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Open AccessReview Serotype Chimeric Human Adenoviruses for Cancer GeneTherapy
Viruses 2010, 2(10), 2196-2212; doi:10.3390/v2102196
Received: 18 June 2010 / Revised: 16 August 2010 / Accepted: 22 September 2010 / Published: 30 September 2010
Cited by 9 | PDF Full-text (170 KB)
Abstract
Cancer gene therapy consists of numerous approaches where the common denominator is utilization of vectors for achieving therapeutic effect. A particularly potent embodiment of the approach is virotherapy, in which the replication potential of an oncolytic virus is directed towards tumor cells to
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Cancer gene therapy consists of numerous approaches where the common denominator is utilization of vectors for achieving therapeutic effect. A particularly potent embodiment of the approach is virotherapy, in which the replication potential of an oncolytic virus is directed towards tumor cells to cause lysis, while normal cells are spared. Importantly, the therapeutic effect of the initial viral load is amplified through viral replication cycles and production of progeny virions. All cancer gene therapy approaches rely on a sufficient level of delivery of the anticancer agent into target cells. Thus,enhancement of delivery to target cells, and reduction of delivery to non-target cells, in an approach called transductional targeting, is attractive. Both genetic and non-genetic retargeting strategies have been utilized. However, in the context of oncolytic viruses, it is beneficial to have the specific modification included in progeny virions and hence genetic modification may be preferable. Serotype chimerism utilizes serotype specific differences in receptor usage, liver tropism and seroprevalence in order to gain enhanced infection of target tissue. This review will focus on serotype chimeric adenoviruses for cancer gene therapy applications. Full article
(This article belongs to the Special Issue Adenoviral Vectors)
Open AccessReview Synthesis and Early Development of Hexadecyloxypropyl-cidofovir: An Oral Antipoxvirus Nucleoside Phosphonate
Viruses 2010, 2(10), 2213-2225; doi:10.3390/v2102213
Received: 26 August 2010 / Revised: 8 September 2010 / Accepted: 8 September 2010 / Published: 30 September 2010
Cited by 27 | PDF Full-text (135 KB)
Abstract
Hexadecyloxypropyl-cidofovir (HDP-CDV) is a novel ether lipid conjugate of (S)-1-(3-hydroxy-2-phosphonoylmethoxypropyl)-cytosine (CDV) which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with CDV. In contrast to CDV, HDP-CDV is orally active and lacks the nephrotoxicity of CDV itself. Increased oral
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Hexadecyloxypropyl-cidofovir (HDP-CDV) is a novel ether lipid conjugate of (S)-1-(3-hydroxy-2-phosphonoylmethoxypropyl)-cytosine (CDV) which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with CDV. In contrast to CDV, HDP-CDV is orally active and lacks the nephrotoxicity of CDV itself. Increased oral bioavailability and increased cellular uptake is facilitated by the lipid portion of the molecule which is responsible for the improved activity profile. The lipid portion of HDP-CDV is cleaved in the cell, releasing CDV which is converted to CDV diphosphate, the active metabolite. HDP-CDV is a highly effective agent against a variety of orthopoxvirus infections in animal models of disease including vaccinia, cowpox, rabbitpox and ectromelia. Its activity was recently demonstrated in a case of human disseminated vaccinia infection after it was added to a multiple drug regimen. In addition to the activity against orthopoxviruses, HDP-CDV (CMX001) is active against all double stranded DNA viruses including CMV, HSV-1, HSV-2, EBV, adenovirus, BK virus, orf, JC, and papilloma viruses, and is under clinical evaluation as a treatment for human infections with these agents. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)
Open AccessReview Friend Spleen Focus-Forming Virus Activates the Tyrosine Kinase sf-Stk and the Transcription Factor PU.1 to Cause a Multi-Stage Erythroleukemia in Mice
Viruses 2010, 2(10), 2235-2257; doi:10.3390/v2102235
Received: 26 August 2010 / Revised: 11 September 2010 / Accepted: 16 September 2010 / Published: 11 October 2010
Cited by 7 | PDF Full-text (378 KB)
Abstract
Hematological malignancies in humans typically involve two types of genetic changes: those that promote hematopoietic cell proliferation and survival (often the result of activation of tyrosine kinases) and those that impair hematopoietic cell differentiation (often the result of changes in transcription factors). The
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Hematological malignancies in humans typically involve two types of genetic changes: those that promote hematopoietic cell proliferation and survival (often the result of activation of tyrosine kinases) and those that impair hematopoietic cell differentiation (often the result of changes in transcription factors). The multi-stage erythroleukemia induced in mice by Friend spleen focus-forming virus (SFFV) is an excellent animal model for studying the molecular basis for both of these changes. Significant progress has been made in understanding the molecular basis for the multi-stage erythroleukemia induced by Friend SFFV. In the first stage of leukemia, the envelope protein encoded by SFFV interacts with and activates the erythropoietin (Epo) receptor and the receptor tyrosine kinase sf-Stk in erythroid cells, causing their Epo-independent proliferation, differentiation and survival. In the second stage, SFFV integration into the Sfpi1 locus activates the myeloid transcription factor PU.1, blocking erythroid cell differentiation, and in conjunction with the loss of p53 tumor suppressor activity, results in the outgrowth of malignant cells. In this review, we discuss the current level of understanding of how SFFV alters the growth and differentiation of erythroid cells and results in the development of erythroleukemia. Our knowledge of how SFFV causes erythroleukemia in mice may give us clues as to how the highly related human retrovirus XMRV causes malignancies in humans. Full article
(This article belongs to the Special Issue Cell Transformation by RNA Viruses)
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Open AccessReview Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors
Viruses 2010, 2(10), 2290-2355; doi:10.3390/v2102290
Received: 2 September 2010 / Accepted: 7 October 2010 / Published: 13 October 2010
Cited by 53 | PDF Full-text (2108 KB)
Abstract
Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans)
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Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications. Full article
(This article belongs to the Special Issue Adenoviral Vectors)
Open AccessReview Poxvirus Exploitation of the Ubiquitin-Proteasome System
Viruses 2010, 2(10), 2356-2380; doi:10.3390/v2102356
Received: 2 September 2010 / Revised: 27 September 2010 / Accepted: 30 September 2010 / Published: 19 October 2010
Cited by 16 | PDF Full-text (549 KB)
Abstract
Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins
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Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins that interact with cullin-3 and cullin-1 based ubiquitin ligases, respectively. Multiple members of the poxvirus family also encode ubiquitin ligases with intrinsic activity. This review describes the numerous mechanisms that poxviruses employ to manipulate the ubiquitin-proteasome system. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
Open AccessReview Therapeutic Vaccines and Antibodies for Treatment of Orthopoxvirus Infections
Viruses 2010, 2(10), 2381-2403; doi:10.3390/v2102381
Received: 19 September 2010 / Revised: 9 October 2010 / Accepted: 13 October 2010 / Published: 20 October 2010
Cited by 6 | PDF Full-text (101 KB)
Abstract
Despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. The current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but
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Despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. The current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but because of safety issues, it is no longer given as a routine vaccine to the general population. In the event of serious human orthopoxvirus infections, it is important to have treatments available for individual patients as well as their close contacts. The smallpox vaccine and vaccinia immune globulin (VIG) were used in the past as therapeutics for patients exposed to smallpox. VIG was also used in patients who were at high risk of developing complications from smallpox vaccination. Thus post-exposure vaccination and VIG treatments may again become important therapeutic modalities. This paper summarizes some of the historic use of the smallpox vaccine and immunoglobulins in the post-exposure setting in humans and reviews in detail the newer animal studies that address the use of therapeutic vaccines and immunoglobulins in orthopoxvirus infections as well as the development of new therapeutic monoclonal antibodies. Full article
(This article belongs to the Special Issue Antivirals Against Poxviruses)

Other

Jump to: Editorial, Research, Review

Open AccessCommentary HIV-1 Tat: Its Dependence on Host Factors is Crystal Clear
Viruses 2010, 2(10), 2226-2234; doi:10.3390/v2102226
Received: 2 September 2010 / Revised: 1 October 2010 / Accepted: 1 October 2010 / Published: 6 October 2010
Cited by 8 | PDF Full-text (200 KB)
Abstract
HIV-1 transcription is regulated at the level of elongation by the viral Tat protein together with the cellular elongation factor P-TEFb, which is composed of cyclin T1 and Cdk9 subunits. The crystal structure of a Tat:P-TEFb complex (Tahirov, T.H.; Babayeva, N.D.; Varzavand, K.;
[...] Read more.
HIV-1 transcription is regulated at the level of elongation by the viral Tat protein together with the cellular elongation factor P-TEFb, which is composed of cyclin T1 and Cdk9 subunits. The crystal structure of a Tat:P-TEFb complex (Tahirov, T.H.; Babayeva, N.D.; Varzavand, K.; Cooper, J.J.; Sedore, S.C.; and Price, D.H. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature 2010, 465, 747-751.) reveals molecular details of Tat and its interactions that have eluded investigators for more than two decades and provides provocative insights into the mechanism of Tat activation. Full article
(This article belongs to the Section Editorial)
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