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Viruses, Volume 4, Issue 8 (August 2012) – 13 articles , Pages 1182-1371

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454 KiB  
Review
Shedding Light on Filovirus Infection with High-Content Imaging
by Gianluca Pegoraro, Sina Bavari and Rekha G. Panchal
Viruses 2012, 4(8), 1354-1371; https://doi.org/10.3390/v4081354 - 23 Aug 2012
Cited by 13 | Viewed by 7246
Abstract
Microscopy has been instrumental in the discovery and characterization of microorganisms. Major advances in high-throughput fluorescence microscopy and automated, high-content image analysis tools are paving the way to the systematic and quantitative study of the molecular properties of cellular systems, both at the [...] Read more.
Microscopy has been instrumental in the discovery and characterization of microorganisms. Major advances in high-throughput fluorescence microscopy and automated, high-content image analysis tools are paving the way to the systematic and quantitative study of the molecular properties of cellular systems, both at the population and at the single-cell level. High-Content Imaging (HCI) has been used to characterize host-virus interactions in genome-wide reverse genetic screens and to identify novel cellular factors implicated in the binding, entry, replication and egress of several pathogenic viruses. Here we present an overview of the most significant applications of HCI in the context of the cell biology of filovirus infection. HCI assays have been recently implemented to quantitatively study filoviruses in cell culture, employing either infectious viruses in a BSL-4 environment or surrogate genetic systems in a BSL-2 environment. These assays are becoming instrumental for small molecule and siRNA screens aimed at the discovery of both cellular therapeutic targets and of compounds with anti-viral properties. We discuss the current practical constraints limiting the implementation of high-throughput biology in a BSL-4 environment, and propose possible solutions to safely perform high-content, high-throughput filovirus infection assays. Finally, we discuss possible novel applications of HCI in the context of filovirus research with particular emphasis on the identification of possible cellular biomarkers of virus infection. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012)
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530 KiB  
Review
Herpesviruses Placating the Unwilling Host: Manipulation of the MHC Class II Antigen Presentation Pathway
by Jianmin Zuo and Martin Rowe
Viruses 2012, 4(8), 1335-1353; https://doi.org/10.3390/v4081335 - 22 Aug 2012
Cited by 22 | Viewed by 10581
Abstract
Lifelong persistent infection by herpesviruses depends on the balance between host immune responses and viral immune evasion. CD4 T cells responding to antigens presented on major histocompatibility complex class II (MHC-II) molecules are known to play an important role in controlling herpesvirus infections. [...] Read more.
Lifelong persistent infection by herpesviruses depends on the balance between host immune responses and viral immune evasion. CD4 T cells responding to antigens presented on major histocompatibility complex class II (MHC-II) molecules are known to play an important role in controlling herpesvirus infections. Here we review, with emphasis on human herpesvirus infections, the strategies evolved to evade CD4 T cell immunity. These viruses target multiple points on the MHC class II antigen presentation pathway. The mechanisms include: suppression of CIITA to inhibit the synthesis of MHC class II molecules, diversion or degradation of HLA-DR molecules during membrane transport, and direct targeting of the invariant chain chaperone of HLA-DR. Full article
(This article belongs to the Special Issue Immune Evasion)
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201 KiB  
Article
Performance of VIDISCA-454 in Feces-Suspensions and Serum
by Michel De Vries, Bas B. Oude Munnink, Martin Deijs, Marta Canuti, Sylvie M. Koekkoek, Richard Molenkamp, Margreet Bakker, Suzanne Jurriaans, Barbera D. C. Van Schaik, Angela C. Luyf, Silvia D. Olabarriaga, Antoine H. C. Van Kampen and Lia Van der Hoek
Viruses 2012, 4(8), 1328-1334; https://doi.org/10.3390/v4081328 - 22 Aug 2012
Cited by 32 | Viewed by 7619
Abstract
Virus discovery combining sequence unbiased amplification with next generation sequencing is now state-of-the-art. We have previously determined that the performance of the unbiased amplification technique which is operational at our institute, VIDISCA-454, is efficient when respiratory samples are used as input. The performance [...] Read more.
Virus discovery combining sequence unbiased amplification with next generation sequencing is now state-of-the-art. We have previously determined that the performance of the unbiased amplification technique which is operational at our institute, VIDISCA-454, is efficient when respiratory samples are used as input. The performance of the assay is, however, not known for other clinical materials like blood or stool samples. Here, we investigated the sensitivity of VIDISCA-454 with feces-suspensions and serum samples that are positive and that have been quantified for norovirus and human immunodeficiency virus type 1, respectively. The performance of VIDISCA-454 in serum samples was equal to its performance in respiratory material, with an estimated lower threshold of 1,000 viral genome copies. The estimated threshold in feces-suspension is around 200,000 viral genome copies. The decreased sensitivity in feces suspension is mainly due to sequences that share no recognizable identity with known sequences. Most likely these sequences originate from bacteria and phages which are not completely sequenced. Full article
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428 KiB  
Article
PAirwise Sequence Comparison (PASC) and Its Application in the Classification of Filoviruses
by Yiming Bao, Vyacheslav Chetvernin and Tatiana Tatusova
Viruses 2012, 4(8), 1318-1327; https://doi.org/10.3390/v4081318 - 20 Aug 2012
Cited by 33 | Viewed by 8101
Abstract
PAirwise Sequence Comparison (PASC) is a tool that uses genome sequence similarity to help with virus classification. The PASC tool at NCBI uses two methods: local alignment based on BLAST and global alignment based on Needleman-Wunsch algorithm. It works for complete genomes of [...] Read more.
PAirwise Sequence Comparison (PASC) is a tool that uses genome sequence similarity to help with virus classification. The PASC tool at NCBI uses two methods: local alignment based on BLAST and global alignment based on Needleman-Wunsch algorithm. It works for complete genomes of viruses of several families/groups, and for the family of Filoviridae, it currently includes 52 complete genomes available in GenBank. It has been shown that BLAST-based alignment approach works better for filoviruses, and therefore is recommended for establishing taxon demarcation criteria. When more genome sequences with high divergence become available, these demarcations will most likely become more precise. The tool can compare new genome sequences of filoviruses with the ones already in the database, and propose their taxonomic classification. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012)
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686 KiB  
Review
A Review of Filovirus Work and Facilities at The Defence Science and Technology Laboratory Porton Down
by Sophie J. Smither and Mark S. Lever
Viruses 2012, 4(8), 1305-1317; https://doi.org/10.3390/v4081305 - 17 Aug 2012
Cited by 7 | Viewed by 9679
Abstract
Porton Down houses two separate sites capable of conducting high containment research on ACDP (Advisory Committee on Dangerous Pathogens) Hazard Group 4 agents: the Defence Science and Technology Laboratory (Dstl) and the Health Protection Agency (HPA), and filovirus research has been performed at [...] Read more.
Porton Down houses two separate sites capable of conducting high containment research on ACDP (Advisory Committee on Dangerous Pathogens) Hazard Group 4 agents: the Defence Science and Technology Laboratory (Dstl) and the Health Protection Agency (HPA), and filovirus research has been performed at Porton Down since the first Marburg virus disease outbreak in 1967. All work is conducted within primary containment either within cabinet lines (for in vitro work) or large rigid half-suit isolators (for in vivo work). There are extensive aerobiological facilities at high containment and the use of these facilities will be reported. Research at Dstl is primarily focused on assessing and quantifying the hazard, and testing the efficacy of medical countermeasures against filoviruses. Fundamental research directed to the study and understanding of the infectious and pathogenic nature of the filoviruses, particularly in aerosols, will be reported. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012)
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1091 KiB  
Article
Whole Genomic Analysis of Human G1P[8] Rotavirus Strains From Different Age Groups in China
by Tsuzumi Shintani, Souvik Ghosh, Yuan-Hong Wang, Xuan Zhou, Dun-Jin Zhou and Nobumichi Kobayashi
Viruses 2012, 4(8), 1289-1304; https://doi.org/10.3390/v4081289 - 16 Aug 2012
Cited by 17 | Viewed by 5976
Abstract
G1P[8] rotaviruses are an important cause of diarrhea in humans in China. To date, there are no reports on the whole genomic analysis of the Chinese G1P[8] rotaviruses. To determine the origin and overall genetic makeup of the recent Chinese G1P[8] strains, the [...] Read more.
G1P[8] rotaviruses are an important cause of diarrhea in humans in China. To date, there are no reports on the whole genomic analysis of the Chinese G1P[8] rotaviruses. To determine the origin and overall genetic makeup of the recent Chinese G1P[8] strains, the whole genomes of three strains, RVA/Human-wt/CHN/E1911/2009/G1P[8], RVA/Human-tc/CHN/R588/2005/G1P[8] and RVA/Human-tc/CHN/Y128/2004/G1P[8], detected in an infant, a child and an adult, respectively, were analyzed. Strains E1911, R588 and Y128 exhibited a typical Wa-like genotype constellation. Except for the NSP3 gene of E1911, the whole genomes of strains E1911, R588 and Y128 were found to be more closely related to those of the recent Wa-like common human strains from different countries than those of the prototype G1P[8] strain, or other old strains. On the other hand, the NSP3 gene of E1911 was genetically distinct from those of Y128, R588, or other Wa-like common human strains, and appeared to share a common origin with those of the porcine-like human G9 strains, providing evidence for intergenotype reassortment events. Comparisons of the amino acid residues defining the VP7 and VP4 antigenic domains revealed several mismatches between these Chinese G1P[8] strains and the G1 and P[8] strains contained in the currently licensed rotavirus vaccines RotarixTM and RotaTeqTM. Full article
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481 KiB  
Communication
A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor
by Života Selaković, Dejan Opsenica, Brett Eaton, Cary Retterer, Sina Bavari, James C. Burnett, Bogdan A. Šolaja and Rekha G. Panchal
Viruses 2012, 4(8), 1279-1288; https://doi.org/10.3390/v4081279 - 15 Aug 2012
Cited by 12 | Viewed by 6572
Abstract
Ebola (EBOV) and Marburg (MARV) filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for [...] Read more.
Ebola (EBOV) and Marburg (MARV) filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for the development of small molecule therapeutics providing immediate antiviral effects. Herein we describe a brief structural exploration of two previously reported diazachrysene (DAAC)-based EBOV inhibitors. Specifically, three analogs were prepared to examine how slight substituent modifications would affect inhibitory efficacy and inhibitor-mediated toxicity during not only EBOV, but also MARV cellular infection. Of the three analogs, one was highly efficacious, providing IC50 values of 0.696 µM ± 0.13 µM and 2.76 µM ± 0.21 µM against EBOV and MARV infection, respectively, with little or no associated cellular toxicity. Overall, the structure-activity and structure-toxicity results from this study provide a framework for the future development of DAAC-based filovirus inhibitors that will be both active and non-toxic in vivo. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012)
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686 KiB  
Article
Roles of ITPA and IL28B Genotypes in Chronic Hepatitis C Patients Treated with Peginterferon Plus Ribavirin
by Tatsuo Miyamura, Tatsuo Kanda, Shingo Nakamoto, Shuang Wu, Xia Jiang, Makoto Arai, Keiichi Fujiwara, Fumio Imazeki and Osamu Yokosuka
Viruses 2012, 4(8), 1264-1278; https://doi.org/10.3390/v4081264 - 14 Aug 2012
Cited by 20 | Viewed by 7560
Abstract
It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how [...] Read more.
It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how ITPA and IL28B genotypes have clinical impacts on treatment-induced hematotoxicities and treatment response in HCV-infected patients treated with peginterferon plus ribavirin. ITPA genotypes (rs1127354 and rs6051702) and IL28B genotype (rs8099917) were determined by TaqMan SNP assay. We compared clinical background, treatment course and treatment response in terms of these genotypes. Only IL28B rs8099917 major type could predict sustained virological response. ITPA rs1127354 major type leads to significantly greater ribavirin-induced anemia than ITPA rs1127354 minor type between days 0 and 84. We noticed that IL28B rs8099917 minor genotype was associated with higher reduction of neutrophils and platelets. ITPA rs1127354 is useful for the prediction of ribavirin-induced anemia in the early phase after the commencement of peginterferon plus ribavirin treatment and IL28B rs8099917 is useful for the prediction of sustained virological response. Use of the combination of these two genotypes could lead to safe and effective treatment of chronic hepatitis C patients. Full article
(This article belongs to the Special Issue Hepatitis C Pathology)
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381 KiB  
Communication
The Role of Equine Herpesvirus Type 4 Glycoprotein K in Virus Replication
by Walid Azab and Abuelyazeed El-Sheikh
Viruses 2012, 4(8), 1258-1263; https://doi.org/10.3390/v4081258 - 07 Aug 2012
Cited by 1 | Viewed by 4857
Abstract
Equine herpesvirus 4 (EHV-4) is an important equine pathogen that causes respiratory tract disease among horses worldwide. Glycoprotein K (gK) homologues have been identified in several alphaherpesviruses as a major player in virus entry, replication, and spread. In the present study, EHV-4 gK-deletion [...] Read more.
Equine herpesvirus 4 (EHV-4) is an important equine pathogen that causes respiratory tract disease among horses worldwide. Glycoprotein K (gK) homologues have been identified in several alphaherpesviruses as a major player in virus entry, replication, and spread. In the present study, EHV-4 gK-deletion mutant has been generated by using bacterial artificial chromosome technology and Red mutagenesis to investigate the role of gK in EHV-4 replication. Our findings reported here show that gK is essential for virus replication in vitro and that the gK-negative strain was not able to be reconstituted in equine cells. It is noteworthy that these findings agree with the previously published study describing gK deletion in other alphaherpesviruses. Full article
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2273 KiB  
Review
Updated Values for Molecular Diagnosis for Highly Pathogenic Avian Influenza Virus
by Akira Sakurai and Futoshi Shibasaki
Viruses 2012, 4(8), 1235-1257; https://doi.org/10.3390/v4081235 - 07 Aug 2012
Cited by 26 | Viewed by 12715
Abstract
Highly pathogenic avian influenza (HPAI) viruses of the H5N1 strain pose a pandemic threat. H5N1 strain virus is extremely lethal and contagious for poultry. Even though mortality is 59% in infected humans, these viruses do not spread efficiently between humans. In 1997, an [...] Read more.
Highly pathogenic avian influenza (HPAI) viruses of the H5N1 strain pose a pandemic threat. H5N1 strain virus is extremely lethal and contagious for poultry. Even though mortality is 59% in infected humans, these viruses do not spread efficiently between humans. In 1997, an outbreak of H5N1 strain with human cases occurred in Hong Kong. This event highlighted the need for rapid identification and subtyping of influenza A viruses (IAV), not only to facilitate surveillance of the pandemic potential of avian IAV, but also to improve the control and treatment of infected patients. Molecular diagnosis has played a key role in the detection and typing of IAV in recent years, spurred by rapid advances in technologies for detection and characterization of viral RNAs and proteins. Such technologies, which include immunochromatography, quantitative real-time PCR, super high-speed real-time PCR, and isothermal DNA amplification, are expected to contribute to faster and easier diagnosis and typing of IAV. Full article
(This article belongs to the Special Issue H5N1 Influenza Virus)
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390 KiB  
Article
Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance
by Barbara A. Rath, Richard A. Olshen, Jerry Halpern and Thomas C. Merigan
Viruses 2012, 4(8), 1212-1234; https://doi.org/10.3390/v4081212 - 07 Aug 2012
Cited by 2 | Viewed by 6823
Abstract
When HIV-1 is exposed to lamivudine (3TC) at inhibitory concentrations, resistant variants carrying the reverse transcriptase (RT) substitution M184V emerge rapidly. This substitution confers high-level 3TC resistance and increased RT fidelity. We established a novel in vitro system to study the effect of [...] Read more.
When HIV-1 is exposed to lamivudine (3TC) at inhibitory concentrations, resistant variants carrying the reverse transcriptase (RT) substitution M184V emerge rapidly. This substitution confers high-level 3TC resistance and increased RT fidelity. We established a novel in vitro system to study the effect of starting nevirapine (NVP) in 3TC-resistant/NNRTI-naïve clinical isolates, and the impact of maintaining versus dropping 3TC pressure in this setting. Because M184V mutant HIV-1 seems hypersusceptible to adefovir (ADV), we also tested the effect of ADV pressure on the same isolates. We draw four conclusions from our experiments simulating combination therapy in vitro. (1) The presence of low-dose (1 μM) 3TC prevented reversal to wild-type from an M184V mutant background. (2) Adding low-dose 3TC in the presence of NVP delayed the selection of NVP-associated mutations. (3) The presence of ADV, in addition to NVP, led to more rapid reversal to wild-type at position 184 than NVP alone. (4) ADV plus NVP selected for greater numbers of mutations than NVP alone. Inference about the “selection of mutation” is based on two statistical models, one at the viral level, more telling, and the other at the level of predominance of mutation within a population. Multidrug pressure experiments lend understanding to mechanisms of HIV resistance as they bear upon new treatment strategies. Full article
(This article belongs to the Special Issue HIV Dynamics and Evolution)
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1209 KiB  
Article
Evaluation of the Operator Protection Factors Offered by Positive Pressure Air Suits against Airborne Microbiological Challenge
by Jackie A. Steward and Mark S. Lever
Viruses 2012, 4(8), 1202-1211; https://doi.org/10.3390/v4081202 - 07 Aug 2012
Cited by 7 | Viewed by 7012
Abstract
Laboratories throughout the world that perform work with Risk Group 4 Pathogens generally adopt one of two approaches within BSL-4 environments: either the use of positive pressure air-fed suits or using Class III microbiological safety cabinets and isolators for animal work. Within the [...] Read more.
Laboratories throughout the world that perform work with Risk Group 4 Pathogens generally adopt one of two approaches within BSL-4 environments: either the use of positive pressure air-fed suits or using Class III microbiological safety cabinets and isolators for animal work. Within the UK at present, all laboratories working with Risk Group 4 agents adopt the use of Class III microbiological safety cabinet lines and isolators. Operator protection factors for the use of microbiological safety cabinets and isolators are available however; there is limited published data on the operator protection factors afforded by the use of positive pressure suits. This study evaluated the operator protection factors provided by positive pressure air suits against a realistic airborne microbiological challenge. The suits were tested, both intact and with their integrity compromised, on an animated mannequin within a stainless steel exposure chamber. The suits gave operator protection in all tests with an intact suit and with a cut in the leg. When compromised by a cut in the glove, a very small ingress of the challenge was seen as far as the wrist. This is likely to be due to the low airflow in the gloves of the suit. In all cases no microbiological penetration of the respiratory tract was observed. These data provide evidence on which to base safety protocols for use of positive pressure suits within high containment laboratories. Full article
(This article belongs to the Special Issue Advances in Filovirus Research 2012)
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311 KiB  
Review
Herpesvirus Exploitation of Host Immune Inhibitory Pathways
by Gabrielle Stack, Maria A. Stacey and Ian R. Humphreys
Viruses 2012, 4(8), 1182-1201; https://doi.org/10.3390/v4081182 - 03 Aug 2012
Cited by 20 | Viewed by 7405
Abstract
Herpesviruses employ a plethora of mechanisms to circumvent clearance by host immune responses. A key feature of mammalian immune systems is the employment of regulatory pathways that limit immune responsiveness. The primary functions of these mechanisms are to control autoimmunity and limit exuberant [...] Read more.
Herpesviruses employ a plethora of mechanisms to circumvent clearance by host immune responses. A key feature of mammalian immune systems is the employment of regulatory pathways that limit immune responsiveness. The primary functions of these mechanisms are to control autoimmunity and limit exuberant responses to harmless antigen in mucosal surfaces. However, such pathways can be exploited by viral pathogens to enable acute infection, persistence and dissemination. Herein, we outline the current understanding of inhibitory pathways in modulating antiviral immunity during herpesvirus infections in vivo and discuss strategies employed by herpesviruses to exploit these pathways to limit host antiviral immunity. Full article
(This article belongs to the Special Issue Immune Evasion)
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