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Viruses, Volume 1, Issue 3 (December 2009), Pages 335-1363

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Research

Jump to: Review

Open AccessArticle Simultaneous Detection of CDC Category "A" DNA and RNA Bioterrorism Agents by Use of Multiplex PCR & RT-PCR Enzyme Hybridization Assays
Viruses 2009, 1(3), 441-459; doi:10.3390/v1030441
Received: 13 July 2009 / Revised: 22 September 2009 / Accepted: 20 October 2009 / Published: 20 October 2009
Cited by 18 | PDF Full-text (174 KB) | HTML Full-text | XML Full-text
Abstract
Assays to simultaneously detect multiple potential agents of bioterrorism are limited. Two multiplex PCR and RT-PCR enzyme hybridization assays (mPCR-EHA, mRT-PCR-EHA) were developed to simultaneously detect many of the CDC category “A” bioterrorism agents. The “Bio T” DNA assay was developed to detect:
[...] Read more.
Assays to simultaneously detect multiple potential agents of bioterrorism are limited. Two multiplex PCR and RT-PCR enzyme hybridization assays (mPCR-EHA, mRT-PCR-EHA) were developed to simultaneously detect many of the CDC category “A” bioterrorism agents. The “Bio T” DNA assay was developed to detect: Variola major (VM), Bacillus anthracis (BA), Yersinia pestis (YP), Francisella tularensis (FT) and Varicella zoster virus (VZV). The “Bio T” RNA assay (mRT-PCR-EHA) was developed to detect: Ebola virus (Ebola), Lassa fever virus (Lassa), Rift Valley fever (RVF), Hantavirus Sin Nombre species (HSN) and dengue virus (serotypes 1-4). Sensitivity and specificity of the 2 assays were tested by using genomic DNA, recombinant plasmid positive controls, RNA transcripts controls, surrogate (spiked) clinical samples and common respiratory pathogens. The analytical sensitivity (limit of detection (LOD)) of the DNA asssay for genomic DNA was 1×100~1×102 copies/mL for BA, FT and YP. The LOD for VZV whole organism was 1×10-2 TCID50/mL. The LOD for recombinant controls ranged from 1×102~1×103copies/mL for BA, FT, YP and VM. The RNA assay demonstrated LOD for RNA transcript controls of 1×104~1×106 copies/mL without extraction and 1×105~1×106 copies/mL with extraction for Ebola, RVF, Lassa and HSN. The LOD for dengue whole organisms was ~1×10-4 dilution for dengue 1 and 2, 1×104 LD50/mL and 1×102 LD50/mL for dengue 3 and 4. The LOD without extraction for recombinant plasmid DNA controls was ~1×103 copies/mL (1.5 input copies/reaction) for Ebola, RVF, Lassa and HSN. No cross-reactivity of primers and probes used in both assays was detected with common respiratory pathogens or between targeted analytes. Clinical sensitivity was estimated using 264 surrogate clinical samples tested with the BioT DNA assay and 549 samples tested with the BioT RNA assay. The clinical specificity is 99.6% and 99.8% for BioT DNA assay and BioT RNA assay, respectively. The surrogate sensitivities of these two assays were 100% (95%CI 83-100) for FT, BA (pX02), YP, VM, VZV, dengue 2,3,4 and 95% (95%CI 75-100) for BA (pX01) and dengue 1 using spiked clinical specimens. The specificity of both BioT multiplex assays on spiked specimens was 100% (95% CI 99-100). Compared to other available assays (culture, serology, PCR, etc.) both the BioT DNA mPCR-EHA and BioT RNA mRT-PCR-EHA are rapid, sensitive and specific assays for detecting many category “A” Bioterrorism agents using a standard thermocycler. Full article
Open AccessArticle Liver Cell Transformation in Chronic HBV Infection
Viruses 2009, 1(3), 630-646; doi:10.3390/v1030630
Received: 27 July 2009 / Revised: 26 October 2009 / Accepted: 29 October 2009 / Published: 30 October 2009
Cited by 4 | PDF Full-text (252 KB) | HTML Full-text | XML Full-text
Abstract
Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome,
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Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular oncogenes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long term effects of viral proteins in enhancing immune-mediated liver disease. In this chapter, we discuss different models of HBV-mediated liver cell transformation based on animal systems of hepadnavirus infection as well as functional studies in hepatocyte and hepatoma cell lines. These studies might help identifying the cellular effectors connecting HBV infection and liver cell transformation. Full article
(This article belongs to the Special Issue Hepatitis Viruses)
Open AccessCommunication Seroconversion to HCoV-NL63 in Rhesus Macaques
Viruses 2009, 1(3), 647-656; doi:10.3390/v1030647
Received: 26 August 2009 / Revised: 28 October 2009 / Accepted: 30 October 2009 / Published: 30 October 2009
Cited by 7 | PDF Full-text (234 KB) | HTML Full-text | XML Full-text
Abstract
HCoV-NL63 is a recently identified respiratory virus. Its pathogenesis has not been fully unraveled because an animal model is currently lacking. Here we examined whether rhesus macaques encounter HCoV-NL63 infections during life, by examining the levels of antibodies to HCoV-NL63 in time. The
[...] Read more.
HCoV-NL63 is a recently identified respiratory virus. Its pathogenesis has not been fully unraveled because an animal model is currently lacking. Here we examined whether rhesus macaques encounter HCoV-NL63 infections during life, by examining the levels of antibodies to HCoV-NL63 in time. The animals were followed for 7 up till 19 years, and in three animals we observed a steep rise in antibodies during follow up, indicative of a natural infection with HCoV-NL63. Full article
(This article belongs to the Special Issue Newly Identified Respiratory Viruses)
Open AccessArticle Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies
Viruses 2009, 1(3), 802-817; doi:10.3390/v1030802
Received: 23 September 2009 / Revised: 3 November 2009 / Accepted: 5 November 2009 / Published: 6 November 2009
Cited by 37 | PDF Full-text (657 KB) | XML Full-text
Abstract
Several human monoclonal antibodies (hmAbs) and antibody fragments, including the best characterized in terms of structure-function b12 and Fab X5, exhibit relatively potent and broad HIV-1 neutralizing activity. However, the elicitation of b12 or b12-like antibodies in vivo by vaccine immunogens based on
[...] Read more.
Several human monoclonal antibodies (hmAbs) and antibody fragments, including the best characterized in terms of structure-function b12 and Fab X5, exhibit relatively potent and broad HIV-1 neutralizing activity. However, the elicitation of b12 or b12-like antibodies in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. B12 is highly divergent from the closest corresponding germline antibody while X5 is less divergent. We have hypothesized that the relatively high degree of specific somatic hypermutations may preclude binding of the HIV-1 envelope glycoprotein (Env) to closest germline antibodies, and that identifying antibodies that are intermediates in the pathways to maturation could help design novel vaccine immunogens to guide the immune system for their enhanced elicitation. In support of this hypothesis we have previously found that a germline-like b12 (monovalent and bivalent scFv as an Fc fusion protein or IgG) lacks measurable binding to an Env as measured by ELISA with a sensitivity in the μM range [1]; here we present evidence confirming and expanding these findings for a panel of Envs. In contrast, a germline-like scFv X5 bound Env with high (nM) affinity. To begin to explore the maturation pathways of these antibodies we identified several possible b12 intermediate antibodies and tested their neutralizing activity. These intermediate antibodies neutralized only some HIV-1 isolates and with relatively weak potency. In contrast, germline-like scFv X5 neutralized a subset of the tested HIV-1 isolates with comparable efficiencies to that of the mature X5. These results could help explain the relatively high immunogenicity of the coreceptor binding site on gp120 and the abundance of CD4-induced (CD4i) antibodies in HIV-1-infected patients (X5 is a CD4i antibody) as well as the maturation pathway of X5. They also can help identify antigens that can bind specifically to b12 germline and intermediate antibodies that together with Envs could be used as a conceptually novel type of candidate vaccines. Such candidate vaccines based on two or more immunogens could help guiding the immune system through complex maturation pathways for elicitation of antibodies that are similar or identical to antibodies with known properties. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessArticle Protection against Mucosal SHIV Challenge by Peptide and Helper-Dependent Adenovirus Vaccines
Viruses 2009, 1(3), 920-938; doi:10.3390/v1030920
Received: 5 October 2009 / Revised: 6 November 2009 / Accepted: 9 November 2009 / Published: 10 November 2009
Cited by 20 | PDF Full-text (580 KB) | XML Full-text
Abstract
Groups of rhesus macaques that had previously been immunized with HIV-1 envelope (env) peptides and first generation adenovirus serotype 5 (FG-Ad5) vaccines expressing the same peptides were immunized intramuscularly three times with helperdependent adenovirus (HD-Ad) vaccines expressing only the HIV-1 envelope from JRFL.
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Groups of rhesus macaques that had previously been immunized with HIV-1 envelope (env) peptides and first generation adenovirus serotype 5 (FG-Ad5) vaccines expressing the same peptides were immunized intramuscularly three times with helperdependent adenovirus (HD-Ad) vaccines expressing only the HIV-1 envelope from JRFL. No gag, pol, or other SHIV genes were used for vaccination. One group of the FG-Ad5-immune animals was immunized three times with HD-Ad5 expressing env. One group was immunized by serotype-switching with HD-Ad6, HD-Ad1, and HD-Ad2 expressing env. Previous work demonstrated that serum antibody levels against env were significantly higher in the serotype-switched group than in the HD-Ad5 group. In this study, neutralizing antibody and T cell responses were compared between the groups before and after rectal challenge with CCR5-tropic SHIV-SF162P3. When serum samples were assayed for neutralizing antibodies, only weak activity was observed. T cell responses against env epitopes were higher in the serotype-switched group. When these animals were challenged rectally with SHIV-SF162P3, both the Ad5 and serotype-switch groups significantly reduced peak viral loads 2 to 10-fold 2 weeks after infection. Peak viral loads were significantly lower for the serotype-switched group as compared to the HD-Ad5-immunized group. Viral loads declined over 18 weeks after infection with some animals viremia reducing nearly 4 logs from the peak. These data demonstrate significant mucosal vaccine effects after immunization with only env antigens. These data also demonstrate HD-Ad vectors are a robust platform for vaccination. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessArticle Complete Nucleotide Analysis of the Structural Genome of the Infectious Bronchitis Virus Strain Md27 Reveals its Mosaic Nature
Viruses 2009, 1(3), 1166-1177; doi:10.3390/v1031166
Received: 13 August 2009 / Revised: 19 November 2009 / Accepted: 1 December 2009 / Published: 4 December 2009
Cited by 5 | PDF Full-text (138 KB) | HTML Full-text | XML Full-text
Abstract
Infectious bronchitis virus (IBV) causes highly contagious respiratory or urogenital tract diseases in chickens. The Maryland 27(Md27) strain was first isolated in 1976 from diseased chicken flocks in the Delmarva Peninsula region. To understand the genetic diversity and phylogenetic relationship of existing strains
[...] Read more.
Infectious bronchitis virus (IBV) causes highly contagious respiratory or urogenital tract diseases in chickens. The Maryland 27(Md27) strain was first isolated in 1976 from diseased chicken flocks in the Delmarva Peninsula region. To understand the genetic diversity and phylogenetic relationship of existing strains with Md27, the complete nucleotide sequence of the 3’end coding region (~7.2 kb) of Md27 was determined and compared with other IBV strains and coronaviruses. It has the same S-3-M-5-N-3’ gene order, as is the case of other IBV strains. The spike gene of Md27 exhibits 97% identity with the SE17 strain. There are deletions at the spike gene, non-coding region between M and 5 genes, and at the 3’untranslated region (UTR), which is different from Ark-like strains. Phylogenetic analysis and sequence alignments demonstrate that Md27 is a chimera containing different gene segments that are most closely related to the SE17, Conn and JMK strains. This current study provides evidence for genomic mutations and intergenic recombination that have taken place in the evolution of IBV strain Md27. Full article
Open AccessCommunication All Known Human Rhinovirus Species Are Present in Sputum Specimens of Military Recruits During Respiratory Infection
Viruses 2009, 1(3), 1178-1189; doi:10.3390/v1031178
Received: 1 September 2009 / Revised: 8 November 2009 / Accepted: 2 December 2009 / Published: 4 December 2009
Cited by 19 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Human rhinoviruses (HRV) are known to cause common cold as well as more complicated respiratory infections. HRV species -A, -B and -C have all been associated with lower respiratory infections and exacerbations of asthma. However, the type distribution of strains connected to different
[...] Read more.
Human rhinoviruses (HRV) are known to cause common cold as well as more complicated respiratory infections. HRV species -A, -B and -C have all been associated with lower respiratory infections and exacerbations of asthma. However, the type distribution of strains connected to different kinds of lower respiratory conditions is not clearly known. We have analysed the presence of HRV in sputum specimens derived from military recruits with and without pre-diagnosed asthma at times of acute respiratory infection (CIAS Study, 2004-2005). The analysis was performed with HRV and HEV real-time RT-PCR assays. Subsequently we studied type distribution of HRV strains by genetic typing in the VP4/VP2 genomic region. In total 146 (38.8%) specimens were HRV-positive and 36 (9.3%) HEV-positive. No difference was found in HRV detection between the asthmatic vs. non-asthmatic patients. Most of the genetically typed strains, 18 (62.1%), belonged to HRV-A, while HRV-B strains constituted five (17.2%) of the HRV-positive strains. HRV-C strain was typed four times from the HRV-positive cases and a HEV-D strain twice. We further typed six HEV positive strains in the partial VP1 region. Three of these belonged to HRV-A and three to HEV-D. HRV-A strains were discovered throughout the study period, while HRV-C strains originated from winter and spring specimens. Interestingly, four out of five typed HRV-B strains originated from the summer season specimens. Full article
(This article belongs to the Special Issue Newly Identified Respiratory Viruses)
Open AccessArticle A Novel Duplex Real-Time Reverse-Transcription PCR Assay for the Detection of Influenza A and the Novel Influenza A(H1N1) Strain
Viruses 2009, 1(3), 1204-1208; doi:10.3390/v1031204
Received: 13 October 2009 / Revised: 28 November 2009 / Accepted: 4 December 2009 / Published: 9 December 2009
Cited by 3 | PDF Full-text (85 KB) | HTML Full-text | XML Full-text
Abstract
Timely implementation of antiviral treatment and other public health based responses are dependent on accurate and rapid diagnosis of the novel pandemic influenza A(H1N1) strain. In this study we developed a duplex real-time PCR (RT-PCR) (dFLU-TM) assay for the simultaneous detection of a
[...] Read more.
Timely implementation of antiviral treatment and other public health based responses are dependent on accurate and rapid diagnosis of the novel pandemic influenza A(H1N1) strain. In this study we developed a duplex real-time PCR (RT-PCR) (dFLU-TM) assay for the simultaneous detection of a broad range of influenza A subtypes and specific detection of the novel H1N1 2009 pandemic strain. The assay was compared to the combined results of two previously described monoplex RT-PCR assays using 183 clinical samples and 10 seasonal influenza A isolates. Overall, the results showed that the dFLU-TM RT-PCR method is suitable for detection of influenza A, including the novel H1N1 pandemic strain, in clinical samples. Full article
(This article belongs to the Special Issue Newly Identified Respiratory Viruses)

Review

Jump to: Research

Open AccessReview A(H5N1) Virus Evolution in South East Asia
Viruses 2009, 1(3), 335-361; doi:10.3390/v1030335
Received: 6 July 2009 / Revised: 2 September 2009 / Accepted: 2 October 2009 / Published: 6 October 2009
Cited by 18 | PDF Full-text (4462 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Highly Pathogenic Avian Influenza (HPAI) H5N1 virus is an ongoing public health and socio-economic challenge, particularly in South East Asia. H5N1 is now endemic in poultry in many countries, and represents a major pandemic threat. Here, we describe the evolution of H5N1 virus
[...] Read more.
Highly Pathogenic Avian Influenza (HPAI) H5N1 virus is an ongoing public health and socio-economic challenge, particularly in South East Asia. H5N1 is now endemic in poultry in many countries, and represents a major pandemic threat. Here, we describe the evolution of H5N1 virus in South East Asia, the reassortment events leading to high genetic diversity in the region, and factors responsible for virus spread. The virus has evolved with genetic variations affecting virulence, drug-resistance, and adaptation to new host species. The constant surveillance of these changes is of primary importance in the global efforts of the scientific community. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)
Figures

Open AccessReview The Natural Selection of Herpesviruses and Virus-Specific NK Cell Receptors
Viruses 2009, 1(3), 362-382; doi:10.3390/v1030362
Received: 14 August 2009 / Revised: 13 October 2009 / Accepted: 13 October 2009 / Published: 13 October 2009
Cited by 27 | PDF Full-text (1017 KB) | HTML Full-text | XML Full-text
Abstract
During the co-evolution of cytomegalovirus (CMV) and natural killer (NK) cells, each has evolved specific tactics in an attempt to prevail. CMV has evolved multiple immune evasion mechanisms to avoid detection by NK cells and other immune cells, leading to chronic infection. Meanwhile,
[...] Read more.
During the co-evolution of cytomegalovirus (CMV) and natural killer (NK) cells, each has evolved specific tactics in an attempt to prevail. CMV has evolved multiple immune evasion mechanisms to avoid detection by NK cells and other immune cells, leading to chronic infection. Meanwhile, the host has evolved virus-specific receptors to counter these evasion strategies. The natural selection of viral genes and host receptors allows us to observe a unique molecular example of "survival of the fittest", as virus and immune cells try to out-maneuver one another or for the virus to achieve détente for optimal dissemination in the population. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview Plasmacytoid Dendritic Cells and the Control of Herpesvirus Infections
Viruses 2009, 1(3), 383-419; doi:10.3390/v1030383
Received: 10 August 2009 / Revised: 1 October 2009 / Accepted: 8 October 2009 / Published: 14 October 2009
Cited by 12 | PDF Full-text (431 KB) | HTML Full-text | XML Full-text
Abstract
Type-I interferons (IFN-I) are cytokines essential for vertebrate antiviral defense, including against herpesviruses. IFN-I have potent direct antiviral activities and also mediate a multiplicity of immunoregulatory functions, which can either promote or dampen antiviral adaptive immune responses. Plasmacytoid dendritic cells (pDCs) are the
[...] Read more.
Type-I interferons (IFN-I) are cytokines essential for vertebrate antiviral defense, including against herpesviruses. IFN-I have potent direct antiviral activities and also mediate a multiplicity of immunoregulatory functions, which can either promote or dampen antiviral adaptive immune responses. Plasmacytoid dendritic cells (pDCs) are the professional producers of IFN-I in response to many viruses, including all of the herpesviruses tested. There is strong evidence that pDCs could play a major role in the initial orchestration of both innate and adaptive antiviral immune responses. Depending on their activation pattern, pDC responses may be either protective or detrimental to the host. Here, we summarize and discuss current knowledge regarding pDC implication in the physiopathology of mouse and human herpesvirus infections, and we discuss how pDC functions could be manipulated in immunotherapeutic settings to promote health over disease. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview Dominant-Negative Proteins in Herpesviruses – From Assigning Gene Function to Intracellular Immunization
Viruses 2009, 1(3), 420-440; doi:10.3390/v1030420
Received: 18 August 2009 / Revised: 19 October 2009 / Accepted: 19 October 2009 / Published: 19 October 2009
Cited by 4 | PDF Full-text (572 KB) | HTML Full-text | XML Full-text
Abstract
Investigating and assigning gene functions of herpesviruses is a process, which profits from consistent technical innovation. Cloning of bacterial artificial chromosomes encoding herpesvirus genomes permits nearly unlimited possibilities in the construction of genetically modified viruses. Targeted or randomized screening approaches allow rapid identification
[...] Read more.
Investigating and assigning gene functions of herpesviruses is a process, which profits from consistent technical innovation. Cloning of bacterial artificial chromosomes encoding herpesvirus genomes permits nearly unlimited possibilities in the construction of genetically modified viruses. Targeted or randomized screening approaches allow rapid identification of essential viral proteins. Nevertheless, mapping of essential genes reveals only limited insight into function. The usage of dominant-negative (DN) proteins has been the tool of choice to dissect functions of proteins during the viral life cycle. DN proteins also facilitate the analysis of host-virus interactions. Finally, DNs serve as starting-point for design of new antiviral strategies. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview Identification of Mouse Cytomegalovirus Resistance Loci by ENU Mutagenesis
Viruses 2009, 1(3), 460-483; doi:10.3390/v1030460
Received: 13 August 2009 / Revised: 19 October 2009 / Accepted: 20 October 2009 / Published: 20 October 2009
Cited by 1 | PDF Full-text (284 KB) | HTML Full-text | XML Full-text
Abstract
Host resistance to infection depends on the efficiency with which innate immune responses keep the infectious agent in check. Innate immunity encompasses components with sensing, signaling and effector properties. These elements with nonredundant functions are encoded by a set of host genes, the
[...] Read more.
Host resistance to infection depends on the efficiency with which innate immune responses keep the infectious agent in check. Innate immunity encompasses components with sensing, signaling and effector properties. These elements with nonredundant functions are encoded by a set of host genes, the resistome. Here, we review our findings concerning the resistome. We have screened randomly mutagenized mice for susceptibility to a natural opportunistic pathogen, the mouse cytomegalovirus. We found that some genes with initially no obvious functions in innate immunity may be critical for host survival to infections, falling into a newly defined category of genes of the resistome. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview HBV and HCV Therapy
Viruses 2009, 1(3), 484-509; doi:10.3390/v1030484
Received: 13 August 2009 / Revised: 8 October 2009 / Accepted: 19 October 2009 / Published: 22 October 2009
Cited by 3 | PDF Full-text (311 KB) | HTML Full-text | XML Full-text
Abstract
One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided.
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One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided. Following the demonstration of a more potent antiviral effect in terms of sustained virological response (SVR) rates, Pegylated-IFN coupled with Ribavirin has become the standard treatment for chronic hepatitis C, with nearly 65% of all treated patients achieving a SVR. Long-term suppression of HBV and eradication of HCV would halt the progression of chronic hepatitis to cirrhosis, hepatocellular carcinoma and liver decompensation. Full article
(This article belongs to the Special Issue Hepatitis Viruses)
Open AccessReview Spontaneous and Engineered Compensatory HSV Mutants that Counteract the Host Antiviral PKR Response
Viruses 2009, 1(3), 510-522; doi:10.3390/v1030510
Received: 24 August 2009 / Revised: 22 October 2009 / Accepted: 22 October 2009 / Published: 22 October 2009
Cited by 4 | PDF Full-text (678 KB) | HTML Full-text | XML Full-text
Abstract
A virulent recombinant HSV lacking the diploid γ134.5 gene (Δγ134.5) have been investigated over the last two decades both for anti-tumor therapy and as vaccine vectors. The first generation vectors, while safe, are incapable of sustained replication in the
[...] Read more.
A virulent recombinant HSV lacking the diploid γ134.5 gene (Δγ134.5) have been investigated over the last two decades both for anti-tumor therapy and as vaccine vectors. The first generation vectors, while safe, are incapable of sustained replication in the majority of treated patients. An interferon inducible host antiviral kinase, protein kinase R (PKR), limits late viral protein synthesis and replication of Δγ134.5 viruses. This review describes the development of new Δγ134.5 vectors, through serial passage selection and direct viral genome engineering, which demonstrate selective PKR evasion in targeted cells and improved viral replication without restoring neurovirulence. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview Activation of the Antiviral Kinase PKR and Viral Countermeasures
Viruses 2009, 1(3), 523-544; doi:10.3390/v1030523
Received: 11 August 2009 / Revised: 26 October 2009 / Accepted: 26 October 2009 / Published: 27 October 2009
Cited by 29 | PDF Full-text (195 KB) | HTML Full-text | XML Full-text
Abstract
The interferon-induced double-stranded (ds)RNA-dependent protein kinase (PKR) limits viral replication by an eIF2α-mediated block of translation. Although many negative-strand RNA viruses activate PKR, the responsible RNAs have long remained elusive, as dsRNA, the canonical activator of PKR, has not been detected in cells
[...] Read more.
The interferon-induced double-stranded (ds)RNA-dependent protein kinase (PKR) limits viral replication by an eIF2α-mediated block of translation. Although many negative-strand RNA viruses activate PKR, the responsible RNAs have long remained elusive, as dsRNA, the canonical activator of PKR, has not been detected in cells infected with such viruses. In this review we focus on the activating RNA molecules of different virus families, in particular the negative-strand RNA viruses. We discuss the recently identified non-canonical activators 5’-triphosphate RNA and the vRNP of influenza virus and give an update on strategies of selected RNA and DNA viruses to prevent activation of PKR. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview Effect of Type-I Interferon on Retroviruses
Viruses 2009, 1(3), 545-573; doi:10.3390/v1030545
Received: 10 August 2009 / Revised: 5 October 2009 / Accepted: 26 October 2009 / Published: 27 October 2009
Cited by 4 | PDF Full-text (582 KB) | HTML Full-text | XML Full-text
Abstract
Type-I interferons (IFN-I) play an important role in the innate immune response to several retroviruses. They seem to be effective in controlling the in vivo infection, though many of the clinical signs of retroviral infection may be due to their continual presence which
[...] Read more.
Type-I interferons (IFN-I) play an important role in the innate immune response to several retroviruses. They seem to be effective in controlling the in vivo infection, though many of the clinical signs of retroviral infection may be due to their continual presence which over-stimulates the immune system and activates apoptosis. IFN-I not only affect the immune system, but also operate directly on virus replication. Most data suggest that the in vitro treatment with IFN-I of retrovirus infected cells inhibits the final stages of virogenesis, avoiding the correct assembly of viral particles and their budding, even though the mechanism is not well understood. However, in some retroviruses IFN-I may also act at a previous stage as some retroviral LTRs posses sequences homologous to the IFNstimulated response element (ISRE). When stimulated, ISREs control viral transcription. HIV-1 displays several mechanisms for evading IFN-I, such as through Tat and Nef. Besides IFN-α and IFN-β, some other type I IFN, such as IFN-τ and IFN-ω, have potent antiviral activity and are promising treatment drugs. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview Antagonism of Innate Immunity by Paramyxovirus Accessory Proteins
Viruses 2009, 1(3), 574-593; doi:10.3390/v1030574
Received: 8 September 2009 / Revised: 22 October 2009 / Accepted: 26 October 2009 / Published: 28 October 2009
Cited by 6 | PDF Full-text (139 KB) | XML Full-text
Abstract
Paramyxovirinae, a subfamily of Paramyxoviridae, are negative strand RNA viruses comprised of many important human and animal pathogens, which share a high degree of genetic and structural homology. The accessory proteins expressed from the P/V/C gene are major factors in the
[...] Read more.
Paramyxovirinae, a subfamily of Paramyxoviridae, are negative strand RNA viruses comprised of many important human and animal pathogens, which share a high degree of genetic and structural homology. The accessory proteins expressed from the P/V/C gene are major factors in the pathogenicity of the viruses, because of their ability to abrogate various facets of type I interferon (IFN) induction and signaling. Most of the paramyxoviruses exhibit a commonality in their ability to antagonize innate immunity by blocking IFN induction and the Jak/STAT pathway. However, the manner in which the accessory proteins inhibit the pathway differs among viruses. Similarly, there are variations in the capability of the viruses to counteract intracellular detectors (RNA helicases, mda-5 and RIG-I). Furthermore, a functional specificity in the antagonism of the IFN response has been reported, suggesting that specificity in the circumvention of innate immunity restricts viral host range. Available evidence indicates that paramyxoviruses employ specific strategies to antagonize the IFN response of their specific hosts, which is one of the major factors that determine viral pathogenicity and host range. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview Herpes Virus Amplicon Vectors
Viruses 2009, 1(3), 594-629; doi:10.3390/v1030594
Received: 30 September 2009 / Revised: 26 October 2009 / Accepted: 29 October 2009 / Published: 29 October 2009
Cited by 13 | PDF Full-text (369 KB) | HTML Full-text | XML Full-text
Abstract
Since its emergence onto the gene therapy scene nearly 25 years ago, the replication-defective Herpes Simplex Virus Type-1 (HSV-1) amplicon has gained significance as a versatile gene transfer platform due to its extensive transgene capacity, widespread cellular tropism, minimal immunogenicity, and its amenability
[...] Read more.
Since its emergence onto the gene therapy scene nearly 25 years ago, the replication-defective Herpes Simplex Virus Type-1 (HSV-1) amplicon has gained significance as a versatile gene transfer platform due to its extensive transgene capacity, widespread cellular tropism, minimal immunogenicity, and its amenability to genetic manipulation. Herein, we detail the recent advances made with respect to the design of the HSV amplicon, its numerous in vitro and in vivo applications, and the current impediments this virus-based gene transfer platform faces as it navigates a challenging path towards future clinical testing. Full article
(This article belongs to the Special Issue Novel Viral Vector Systems for Gene Therapy)
Open AccessReview Revisiting Plus-Strand DNA Synthesis in Retroviruses and Long Terminal Repeat Retrotransposons: Dynamics of Enzyme: Substrate Interactions
Viruses 2009, 1(3), 657-677; doi:10.3390/v1030657
Received: 10 September 2009 / Revised: 28 October 2009 / Accepted: 4 November 2009 / Published: 4 November 2009
Cited by 3 | PDF Full-text (791 KB) | HTML Full-text | XML Full-text
Abstract
Although polypurine tract (PPT)-primed initiation of plus-strand DNA synthesis in retroviruses and LTR-containing retrotransposons can be accurately duplicated, the molecular details underlying this concerted series of events remain largely unknown. Importantly, the PPT 3’ terminus must be accommodated by ribonuclease H (RNase H)
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Although polypurine tract (PPT)-primed initiation of plus-strand DNA synthesis in retroviruses and LTR-containing retrotransposons can be accurately duplicated, the molecular details underlying this concerted series of events remain largely unknown. Importantly, the PPT 3’ terminus must be accommodated by ribonuclease H (RNase H) and DNA polymerase catalytic centers situated at either terminus of the cognate reverse transcriptase (RT), and in the case of the HIV-1 enzyme, ~70Å apart. Communication between RT and the RNA/DNA hybrid therefore appears necessary to promote these events. The crystal structure of the HIV-1 RT/PPT complex, while informative, positions the RNase H active site several bases pairs from the PPT/U3 junction, and thus provides limited information on cleavage specificity. To fill the gap between biochemical and crystallographic approaches, we review a multidisciplinary approach combining chemical probing, mass spectrometry, NMR spectroscopy and single molecule spectroscopy. Our studies also indicate that nonnucleoside RT inhibitors affect enzyme orientation, suggesting initiation of plus-strand DNA synthesis as a potential therapeutic target. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
Open AccessReview WU Polyomavirus (WUPyV): A Recently Detected Virus Causing Respiratory Disease?
Viruses 2009, 1(3), 678-688; doi:10.3390/v1030678
Received: 20 August 2009 / Revised: 19 October 2009 / Accepted: 4 November 2009 / Published: 4 November 2009
PDF Full-text (49 KB) | HTML Full-text | XML Full-text
Abstract
The WU polyomavirus (WUPyV) is a novel member of the family Polyomaviridae recently detected in respiratory tract specimens by shotgun sequencing. Intriguingly, viral genome has been detected in 0.4% to 11.5% of respiratory tract specimens from children with respiratory disease. The levels
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The WU polyomavirus (WUPyV) is a novel member of the family Polyomaviridae recently detected in respiratory tract specimens by shotgun sequencing. Intriguingly, viral genome has been detected in 0.4% to 11.5% of respiratory tract specimens from children with respiratory disease. The levels of co-infection with established respiratory viruses were in the range between 30.8% and 91.7%. Moreover, some studies report detection of WUPyV in stool or serum. So far, WUPyV infections can not be distinguished from other viral infections by means of clinical symptoms. Respiratory tract disease like pneumonia or bronchitis is frequently observed in patients harbouring WUPyV. Detection of viremia suggests systemic infections. However, the available data do not prove WUPyV to be a human pathogen. Further investigations are necessary. Full article
(This article belongs to the Special Issue Newly Identified Respiratory Viruses)
Open AccessReview Murine Coronavirus Cell Type Dependent Interaction with the Type I Interferon Response
Viruses 2009, 1(3), 689-712; doi:10.3390/v1030689
Received: 2 September 2009 / Revised: 30 October 2009 / Accepted: 4 November 2009 / Published: 4 November 2009
Cited by 14 | PDF Full-text (352 KB) | HTML Full-text | XML Full-text
Abstract
Coronaviruses infect many species of animal including humans, causing acute and chronic diseases of many organ systems. Murine coronavirus, mouse hepatitis virus (MHV) infection of the mouse, provides animal models for the study of central nervous system disease, including encephalitis and demyelinating diseases
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Coronaviruses infect many species of animal including humans, causing acute and chronic diseases of many organ systems. Murine coronavirus, mouse hepatitis virus (MHV) infection of the mouse, provides animal models for the study of central nervous system disease, including encephalitis and demyelinating diseases such as Multiple Sclerosis and for hepatitis. While there are many studies of the adaptive immune response to MHV, there has until recently been scant information on the type I interferon (IFN) response to MHV. The relationship between MHV and the IFN-α/β response is paradoxical. While the type I IFN response is a crucial aspect of host defense against MHV in its natural host, there is little if any induction of IFN following infection of mouse fibroblast cell lines in vitro. Furthermore, MHV is relatively resistant to the antiviral effects of IFN-α/β in mouse fibroblast cell lines and in human 293T cells. MHV can, under some circumstances, compromise the antiviral effects of IFN signaling. The nucleocapsid protein as well as the nsp1 and nsp3 proteins of MHV has been reported to have IFN antagonist activity. However, in primary cell types such as plasmacytoid dendritic cells (pDC) and macrophages, IFN is induced by MHV infection and an antiviral state is established. Other primary cell types such as neurons, astrocytes and hepatocytes fail to produce IFN following infection and, in vivo, likely depend on IFN produced by pDCs and macrophages for protection from MHV. Thus MHV induction of IFN-α/β and the ability to induce an antiviral state in response to interferon is extremely cell type dependent. IFN induced protection from MHV pathogenesis likely requires the orchestrated activities of several cell types, however, the cell types involved in limiting MHV replication may be different in the liver and in the immune privileged CNS. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview HIV-1 Integrase-DNA Recognition Mechanisms
Viruses 2009, 1(3), 713-736; doi:10.3390/v1030713
Received: 30 September 2009 / Revised: 3 November 2009 / Accepted: 4 November 2009 / Published: 5 November 2009
Cited by 6 | PDF Full-text (336 KB) | HTML Full-text | XML Full-text
Abstract
Integration of a reverse transcribed DNA copy of the HIV viral genome into the host chromosome is essential for virus replication. This process is catalyzed by the virally encoded protein integrase. The catalytic activities, which involve DNA cutting and joining steps, have been
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Integration of a reverse transcribed DNA copy of the HIV viral genome into the host chromosome is essential for virus replication. This process is catalyzed by the virally encoded protein integrase. The catalytic activities, which involve DNA cutting and joining steps, have been recapitulated in vitro using recombinant integrase and synthetic DNA substrates. Biochemical and biophysical studies of these model reactions have been pivotal in advancing our understanding of mechanistic details for how IN interacts with viral and target DNAs, and are the focus of the present review. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
Open AccessReview Activation and Evasion of Innate Antiviral Immunity by Herpes Simplex Virus
Viruses 2009, 1(3), 737-759; doi:10.3390/v1030737
Received: 17 August 2009 / Revised: 3 November 2009 / Accepted: 5 November 2009 / Published: 5 November 2009
Cited by 13 | PDF Full-text (196 KB) | HTML Full-text | XML Full-text
Abstract
Herpes simplex virus (HSV), a human pathogenic virus, has evolved several strategies to evade the production and function of interferons (IFNs) and cytokines generated by the innate immune system to restrict the virus. Equilibrium exists between the virus and the immune response, and
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Herpes simplex virus (HSV), a human pathogenic virus, has evolved several strategies to evade the production and function of interferons (IFNs) and cytokines generated by the innate immune system to restrict the virus. Equilibrium exists between the virus and the immune response, and a shift in this delicate balance either restricts the virus or enhances virus spread and tissue damage. Therefore, understanding of the cytokine response generated after HSV infection and the underlying virus-cell interactions is essential to improve our understanding of viral pathogenesis. This review summarizes the current knowledge on induction and evasion of the innate immune response by HSV. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview The Human Cytomegalovirus Major Immediate-Early Proteins as Antagonists of Intrinsic and Innate Antiviral Host Responses
Viruses 2009, 1(3), 760-779; doi:10.3390/v1030760
Received: 18 August 2009 / Revised: 4 November 2009 / Accepted: 5 November 2009 / Published: 5 November 2009
Cited by 11 | PDF Full-text (144 KB) | HTML Full-text | XML Full-text
Abstract
The major immediate-early (IE) gene of human cytomegalovirus (CMV) is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency. Although a variety of gene products are expressed from this region, the
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The major immediate-early (IE) gene of human cytomegalovirus (CMV) is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency. Although a variety of gene products are expressed from this region, the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant and important. Both proteins have long been recognized as promiscuous transcriptional regulators. More recently, a critical role of the IE1 and IE2 proteins in counteracting nonadaptive host cell defense mechanisms has been revealed. In this review we will briefly summarize the available literature on IE1- and IE2-dependent mechanisms contributing to CMV evasion from intrinsic and innate immune responses. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview The Interaction Between Lentiviral Integrase and LEDGF: Structural and Functional Insights
Viruses 2009, 1(3), 780-801; doi:10.3390/v1030780
Received: 12 October 2009 / Revised: 28 October 2009 / Accepted: 6 November 2009 / Published: 6 November 2009
Cited by 15 | PDF Full-text (453 KB) | HTML Full-text | XML Full-text
Abstract
Since its initial description as an HIV-1 integrase (IN) interactor seven years ago, LEDGF has become one of the best-characterized host factors involved in viral replication. Results of intensive studies in several laboratories indicated that the protein serves as a targeting factor for
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Since its initial description as an HIV-1 integrase (IN) interactor seven years ago, LEDGF has become one of the best-characterized host factors involved in viral replication. Results of intensive studies in several laboratories indicated that the protein serves as a targeting factor for the lentiviral DNA integration machinery, and accounts for the characteristic preference of Lentivirus to integrate within active transcription units. The IN-LEDGF interaction has been put forward as a promising target for antiretroviral drug development and as a potential tool to improve safety of lentiviral vectors for use in gene therapy. Additionally, as a natural ligand of lentiviral IN proteins, LEDGF has been successfully used in structural biology studies of retroviral DNA integration. This review focuses on the structural aspects of the IN-LEDGF interaction and their functional consequences. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
Open AccessReview Hepatitis Delta Virus RNA Replication
Viruses 2009, 1(3), 818-831; doi:10.3390/v1030818
Received: 28 September 2009 / Revised: 3 November 2009 / Accepted: 3 November 2009 / Published: 6 November 2009
Cited by 24 | PDF Full-text (149 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis delta virus (HDV) is a distant relative of plant viroids in the animal world. Similar to plant viroids, HDV replicates its circular RNA genome using a double rolling-circle mechanism. Nevertheless, the production of hepatitis delta antigen (HDAg), which is indispensible for HDV
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Hepatitis delta virus (HDV) is a distant relative of plant viroids in the animal world. Similar to plant viroids, HDV replicates its circular RNA genome using a double rolling-circle mechanism. Nevertheless, the production of hepatitis delta antigen (HDAg), which is indispensible for HDV replication, is a unique feature distinct from plant viroids, which do not encode any protein. Here the HDV RNA replication cycle is reviewed, with emphasis on the function of HDAg in modulating RNA replication and the nature of the enzyme involved. Full article
(This article belongs to the Special Issue Subviral RNAs)
Open AccessReview Interferon Response and Viral Evasion by Members of the Family Rhabdoviridae
Viruses 2009, 1(3), 832-851; doi:10.3390/v1030832
Received: 18 September 2009 / Revised: 5 November 2009 / Accepted: 9 November 2009 / Published: 9 November 2009
Cited by 24 | PDF Full-text (90 KB) | HTML Full-text | XML Full-text
Abstract
Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been
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Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV) and rabies virus (RABV). Despite their structural similarities, VSV and RABV have completely different mechanisms by which they avert the host immune response. VSV relies on the matrix protein to interfere with host gene transcription and nuclear export of anti-viral mRNAs. Alternatively, RABV uses its phosphoprotein to interfere with IRF-3 phosphorylation and STAT1 signaling. Understanding the virus-cell interactions and viral proteins necessary to evade the immune response is important in developing effective vaccines and therapeutics for this viral family. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview Molecular Mechanisms Underlying Hepatocellular Carcinoma
Viruses 2009, 1(3), 852-872; doi:10.3390/v1030852
Received: 14 August 2009 / Revised: 3 November 2009 / Accepted: 9 November 2009 / Published: 9 November 2009
Cited by 16 | PDF Full-text (156 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem
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Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis. Full article
(This article belongs to the Special Issue Hepatitis Viruses)
Open AccessReview Reverse Transcriptase and Cellular Factors: Regulators of HIV-1 Reverse Transcription
Viruses 2009, 1(3), 873-894; doi:10.3390/v1030873
Received: 30 September 2009 / Revised: 6 November 2009 / Accepted: 9 November 2009 / Published: 10 November 2009
Cited by 16 | PDF Full-text (593 KB) | HTML Full-text | XML Full-text
Abstract
There is ample evidence that synthesis of HIV-1 proviral DNA from the viral RNA genome during reverse transcription requires host factors. However, only a few cellular proteins have been described in detail that affect reverse transcription and interact with reverse transcriptase (RT). HIV-1
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There is ample evidence that synthesis of HIV-1 proviral DNA from the viral RNA genome during reverse transcription requires host factors. However, only a few cellular proteins have been described in detail that affect reverse transcription and interact with reverse transcriptase (RT). HIV-1 integrase is an RT binding protein and a number of IN-binding proteins including INI1, components of the Sin3a complex, and Gemin2 affect reverse transcription. In addition, recent studies implicate the cellular proteins HuR, AKAP149, and DNA topoisomerase I in reverse transcription through an interaction with RT. In this review we will consider interactions of reverse transcription complex with viral and cellular factors and how they affect the reverse transcription process. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
Open AccessReview Defective Interfering RNAs: Foes of Viruses and Friends of Virologists
Viruses 2009, 1(3), 895-919; doi:10.3390/v1030895
Received: 20 October 2009 / Revised: 9 November 2009 / Accepted: 9 November 2009 / Published: 10 November 2009
Cited by 32 | PDF Full-text (487 KB) | HTML Full-text | XML Full-text
Abstract
Defective interfering (DI) RNAs are subviral RNAs produced during multiplication of RNA viruses by the error-prone viral replicase. DI-RNAs are parasitic RNAs that are derived from and associated with the parent virus, taking advantage of viral-coded protein factors for their multiplication. Recent advances
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Defective interfering (DI) RNAs are subviral RNAs produced during multiplication of RNA viruses by the error-prone viral replicase. DI-RNAs are parasitic RNAs that are derived from and associated with the parent virus, taking advantage of viral-coded protein factors for their multiplication. Recent advances in the field of DI RNA biology has led to a greater understanding about generation and evolution of DI-RNAs as well as the mechanism of symptom attenuation. Moreover, DI-RNAs are versatile tools in the hands of virologists and are used as less complex surrogate templates to understand the biology of their helper viruses. The ease of their genetic manipulation has resulted in rapid discoveries on cis-acting RNA replication elements required for replication and recombination. DI-RNAs have been further exploited to discover host factors that modulate Tomato bushy stunt virus replication, as well as viral RNA recombination. This review discusses the current models on generation and evolution of DI-RNAs, the roles of viral and host factors in DI-RNA replication, and the mechanisms of disease attenuation. Full article
(This article belongs to the Special Issue Subviral RNAs)
Open AccessReview Therapeutic Approaches Using Host Defence Peptides to Tackle Herpes Virus Infections
Viruses 2009, 1(3), 939-964; doi:10.3390/v1030939
Received: 24 July 2009 / Revised: 11 October 2009 / Accepted: 16 November 2009 / Published: 18 November 2009
Cited by 11 | PDF Full-text (593 KB) | HTML Full-text | XML Full-text
Abstract
One of the most common viral infections in humans is caused by herpes simplex virus (HSV). It can easily be treated with nucleoside analogues (e.g., acyclovir), but resistant strains are on the rise. Naturally occurring antimicrobial peptides have been demonstrated to possess antiviral
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One of the most common viral infections in humans is caused by herpes simplex virus (HSV). It can easily be treated with nucleoside analogues (e.g., acyclovir), but resistant strains are on the rise. Naturally occurring antimicrobial peptides have been demonstrated to possess antiviral activity against HSV. New evidence has also indicated that these host defence peptides are able to selectively stimulate the innate immune system to fight of infections. This review will focus on the anti-HSV activity of such peptides (both natural and synthetic), describe their mode of action and their clinical potential. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview Cellular Players in the Herpes Simplex Virus Dependent Apoptosis Balancing Act
Viruses 2009, 1(3), 965-978; doi:10.3390/v1030965
Received: 30 September 2009 / Revised: 16 November 2009 / Accepted: 17 November 2009 / Published: 18 November 2009
Cited by 7 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis is triggered as an intrinsic defense against numerous viral infections. Almost every virus encodes apoptotic modulators, and the herpes simplex viruses (HSV) are no exception. During HSV infection, there is an intricate balance between pro- and anti-apoptotic factors that delays apoptotic death
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Apoptosis is triggered as an intrinsic defense against numerous viral infections. Almost every virus encodes apoptotic modulators, and the herpes simplex viruses (HSV) are no exception. During HSV infection, there is an intricate balance between pro- and anti-apoptotic factors that delays apoptotic death until the virus has replicated. Perturbations in the apoptotic balance can cause premature cell death and have the potential to dramatically alter the outcome of infection. Recently, certain cellular genes have been shown to regulate sensitivity to HSV-dependent apoptosis. This review summarizes current knowledge of the cellular genes that impact the apoptotic balance during HSV infection. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
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Open AccessReview Innate and Adaptive Immune Responses to Herpes Simplex Virus
Viruses 2009, 1(3), 979-1002; doi:10.3390/v1030979
Received: 30 July 2009 / Revised: 13 November 2009 / Accepted: 16 November 2009 / Published: 18 November 2009
Cited by 34 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
Immune responses against HSV-1 and HSV-2 are complex and involve a delicate interplay between innate signaling pathways and adaptive immune responses. The innate response to HSV involves the induction of type I IFN, whose role in protection against disease is well characterized in
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Immune responses against HSV-1 and HSV-2 are complex and involve a delicate interplay between innate signaling pathways and adaptive immune responses. The innate response to HSV involves the induction of type I IFN, whose role in protection against disease is well characterized in vitro and in vivo. Cell types such as NK cells and pDCs contribute to innate anti-HSV responses in vivo. Finally, the adaptive response includes both humoral and cellular components that play important roles in antiviral control and latency. This review summarizes the innate and adaptive effectors that contribute to susceptibility, immune control and pathogenesis of HSV, and highlights the delicate interplay between these two important arms of immunity. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
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Open AccessReview Bunyaviruses and the Type I Interferon System
Viruses 2009, 1(3), 1003-1021; doi:10.3390/v1031003
Received: 21 September 2009 / Revised: 11 November 2009 / Accepted: 20 November 2009 / Published: 23 November 2009
Cited by 28 | PDF Full-text (98 KB) | HTML Full-text | XML Full-text
Abstract
The family Bunyaviridae contains more than 350 viruses that are distributed throughout the world. Most members of the family are transmitted by arthopods, and several cause disease in man, domesticated animals and crop plants. Despite being recognized as an emerging threat, details of
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The family Bunyaviridae contains more than 350 viruses that are distributed throughout the world. Most members of the family are transmitted by arthopods, and several cause disease in man, domesticated animals and crop plants. Despite being recognized as an emerging threat, details of the virulence mechanisms employed by bunyaviruses are scant. In this article we summarise the information currently available on how these viruses are able to establish infection when confronted with a powerful antiviral interferon system. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview Dendritic Cells in Innate and Adaptive Immune Responses against Influenza Virus
Viruses 2009, 1(3), 1022-1034; doi:10.3390/v1031022
Received: 23 September 2009 / Accepted: 23 November 2009 / Published: 24 November 2009
Cited by 9 | PDF Full-text (78 KB) | HTML Full-text | XML Full-text
Abstract
Dendritic cells (DC) are major players in both innate and adaptive immune responses against influenza virus. These immune responses, as well as the important interface between the innate and adaptive systems, are orchestrated by specialized subsets of DC, including conventional steady-state DC, migratory
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Dendritic cells (DC) are major players in both innate and adaptive immune responses against influenza virus. These immune responses, as well as the important interface between the innate and adaptive systems, are orchestrated by specialized subsets of DC, including conventional steady-state DC, migratory DC and plasmacytoid DC. The characteristics and efficacy of the responses are dependent on the relative activity of these DC subsets, rendering DC crucial for the development of both naïve and memory immune responses. However, due to their critical role, DC also contribute to the immunopathological processes observed during acute influenza, such as that caused by the pathogenic H5N1 viruses. Therein, the role of different DC subsets in the induction of interferon type I, proinflammatory cytokine and chemokine responses is important for the outcome of interaction between the virus and host immune defences. The present review will present current knowledge on this area, relating to the importance of DC activity for the induction of efficacious humoral and cell-mediated immune responses. This will include the main viral elements associated with the triggering or inhibition of DC activation. Finally, the current knowledge on understanding how differences in various vaccines influence the manner of immune defence induction will be presented. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)
Open AccessReview Rotavirus Antagonism of the Innate Immune Response
Viruses 2009, 1(3), 1035-1056; doi:10.3390/v1031035
Received: 14 September 2009 / Revised: 5 November 2009 / Accepted: 20 November 2009 / Published: 24 November 2009
Cited by 8 | PDF Full-text (764 KB) | HTML Full-text | XML Full-text
Abstract
Rotavirus is a primary cause of severe dehydrating gastroenteritis in infants and young children. The virus is sensitive to the antiviral effects triggered by the interferon (IFN)-signaling pathway, an important component of the host cell innate immune response. To counteract these effects, rotavirus
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Rotavirus is a primary cause of severe dehydrating gastroenteritis in infants and young children. The virus is sensitive to the antiviral effects triggered by the interferon (IFN)-signaling pathway, an important component of the host cell innate immune response. To counteract these effects, rotavirus encodes a nonstructural protein (NSP1) that induces the degradation of proteins involved in regulating IFN expression, such as members of the IFN regulatory factor (IRF) family. In some instances, NSP1 also subverts IFN expression by causing the degradation of a component of the E3 ubiquitin ligase complex responsible for activating NF-κB. By antagonizing multiple components of the IFN-induction pathway, NSP1 aids viral spread and contributes to rotavirus pathogenesis. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview A Closer Look at the NS1 of Influenza Virus
Viruses 2009, 1(3), 1057-1072; doi:10.3390/v1031057
Received: 10 September 2009 / Revised: 13 November 2009 / Accepted: 25 November 2009 / Published: 26 November 2009
Cited by 26 | PDF Full-text (135 KB) | HTML Full-text | XML Full-text
Abstract
The Non-Structural 1 (NS1) protein is a multifactorial protein of type A influenza viruses that plays an important role in the virulence of the virus. A large amount of what we know about this protein has been obtained from studies using human influenza
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The Non-Structural 1 (NS1) protein is a multifactorial protein of type A influenza viruses that plays an important role in the virulence of the virus. A large amount of what we know about this protein has been obtained from studies using human influenza isolates and, consequently, the human NS1 protein. The current global interest in avian influenza, however, has highlighted a number of sequence and functional differences between the human and avian NS1. This review discusses these differences in addition to describing potential uses of NS1 in the management and control of avian influenza outbreaks. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)
Open AccessReview HCV Innate Immune Responses
Viruses 2009, 1(3), 1073-1088; doi:10.3390/v1031073
Received: 27 August 2009 / Revised: 25 November 2009 / Accepted: 26 November 2009 / Published: 30 November 2009
Cited by 3 | PDF Full-text (396 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) establishes a persistent infection in more than 70% of infected individuals. This striking ability to evade the powerful innate immune system results from viral interference occurring at several levels of the interferon (IFN) system. There is strong evidence from
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Hepatitis C virus (HCV) establishes a persistent infection in more than 70% of infected individuals. This striking ability to evade the powerful innate immune system results from viral interference occurring at several levels of the interferon (IFN) system. There is strong evidence from cell culture experiments that HCV can inhibit the induction of IFNβ by cleaving important proteins in the virus sensory pathways of cells such as MAVS and TRIF. There is also evidence that HCV interferes with IFNα signaling through the Jak-STAT pathway, and that HCV proteins target IFN effector systems such as protein kinase R (PKR). These in vitro findings will have to be confirmed in clinical trials investigating the molecular mechanisms of HCV interference with the innate immune system in liver samples. Full article
(This article belongs to the Special Issue Hepatitis Viruses)
Open AccessReview Pandemic Influenza Vaccines – The Challenges
Viruses 2009, 1(3), 1089-1109; doi:10.3390/v1031089
Received: 14 August 2009 / Revised: 26 November 2009 / Accepted: 1 December 2009 / Published: 3 December 2009
Cited by 7 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
Recent years’ enzootic spread of highly pathogenic H5N1 virus among poultry and the many lethal zoonoses in its wake has stimulated basic and applied pandemic vaccine research. The quest for an efficacious, affordable and timely accessible pandemic vaccine has been high on the
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Recent years’ enzootic spread of highly pathogenic H5N1 virus among poultry and the many lethal zoonoses in its wake has stimulated basic and applied pandemic vaccine research. The quest for an efficacious, affordable and timely accessible pandemic vaccine has been high on the agenda. When a variant H1N1 strain of swine origin emerged as a pandemic virus, it surprised many, as this subtype is well-known to man as a seasonal virus. This review will cover some difficult vaccine questions, such as the immunological challenges, the new production platforms, and the limited supply and global equity issues. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)
Open AccessReview HIV-1 Protease: Structural Perspectives on Drug Resistance
Viruses 2009, 1(3), 1110-1136; doi:10.3390/v1031110
Received: 1 October 2009 / Revised: 30 November 2009 / Accepted: 1 December 2009 / Published: 3 December 2009
Cited by 46 | PDF Full-text (1295 KB)
Abstract
Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of
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Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
Open AccessReview Mutation Rates and Intrinsic Fidelity of Retroviral Reverse Transcriptases
Viruses 2009, 1(3), 1137-1165; doi:10.3390/v1031137
Received: 20 October 2009 / Revised: 3 December 2009 / Accepted: 3 December 2009 / Published: 4 December 2009
Cited by 40 | PDF Full-text (665 KB) | HTML Full-text | XML Full-text
Abstract
Retroviruses are RNA viruses that replicate through a DNA intermediate, in a process catalyzed by the viral reverse transcriptase (RT). Although cellular polymerases and host factors contribute to retroviral mutagenesis, the RT errors play a major role in retroviral mutation. RT mutations that
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Retroviruses are RNA viruses that replicate through a DNA intermediate, in a process catalyzed by the viral reverse transcriptase (RT). Although cellular polymerases and host factors contribute to retroviral mutagenesis, the RT errors play a major role in retroviral mutation. RT mutations that affect the accuracy of the viral polymerase have been identified by in vitro analysis of the fidelity of DNA synthesis, by using enzymological (gel-based) and genetic assays (e.g., M13mp2 lacZ forward mutation assays). For several amino acid substitutions, these observations have been confirmed in cell culture using viral vectors. This review provides an update on studies leading to the identification of the major components of the fidelity center in retroviral RTs. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
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Open AccessReview Henipaviruses Employ a Multifaceted Approach to Evade the Antiviral Interferon Response
Viruses 2009, 1(3), 1190-1203; doi:10.3390/v1031190
Received: 2 October 2009 / Revised: 2 December 2009 / Accepted: 3 December 2009 / Published: 8 December 2009
Cited by 6 | PDF Full-text (397 KB) | HTML Full-text | XML Full-text
Abstract
Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other paramyxoviruses, their ability to evade the
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Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other paramyxoviruses, their ability to evade the host interferon (IFN) response is conferred by the P gene. The henipavirus P gene encodes four proteins; the P, V, W and C proteins, which have all been described to inhibit the antiviral response. Further studies have revealed that these proteins have overlapping but unique properties which enable the virus to block multiple signaling pathways in the IFN response. The best characterized of these is the JAK-STAT signaling pathway which is targeted by the P, V and W proteins via an interaction with the transcription factor STAT1. In addition the V and W proteins can both limit virus-induced induction of IFN but they appear to do this via distinct mechanisms that rely on unique sequences in their C-terminal domains. The ability to generate recombinant Nipah viruses now gives us the opportunity to determine the precise role for each of these proteins and address their contribution to pathogenicity. Additionally, the question of whether these multiple anti-IFN strategies are all active in the different mammalian hosts for henipaviruses, particularly the fruit bat reservoir, warrants further exploration. Full article
(This article belongs to the Special Issue Interferon Antiviral Response and Viral Evasion)
Open AccessReview Current and Novel Inhibitors of HIV Protease
Viruses 2009, 1(3), 1209-1239; doi:10.3390/v1031209
Received: 8 October 2009 / Revised: 7 December 2009 / Accepted: 7 December 2009 / Published: 11 December 2009
Cited by 50 | PDF Full-text (1044 KB) | HTML Full-text | XML Full-text
Abstract
The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in
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The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR. The potential of these novel compounds to open new way to the rational drug design of human viruses is critically assessed. Full article
(This article belongs to the Special Issue Retroviral Enzymes)
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Open AccessReview Interplay between Herpesvirus Infection and Host Defense by PML Nuclear Bodies
Viruses 2009, 1(3), 1240-1264; doi:10.3390/v1031240
Received: 18 November 2009 / Revised: 10 December 2009 / Accepted: 14 December 2009 / Published: 15 December 2009
Cited by 36 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
In recent studies we and others have identified the cellular proteins PML, hDaxx, and Sp100, which form a subnuclear structure known as nuclear domain 10 (ND10) or PML nuclear bodies (PML-NBs), as host restriction factors that counteract herpesviral infections by inhibiting viral replication
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In recent studies we and others have identified the cellular proteins PML, hDaxx, and Sp100, which form a subnuclear structure known as nuclear domain 10 (ND10) or PML nuclear bodies (PML-NBs), as host restriction factors that counteract herpesviral infections by inhibiting viral replication at different stages. The antiviral function of ND10, however, is antagonized by viral regulatory proteins (e.g., ICP0 of herpes simplex virus; IE1 of human cytomegalovirus) which induce either a modification or disruption of ND10. This review will summarize the current knowledge on how viral replication is inhibited by ND10 proteins. Furthermore, herpesviral strategies to defeat this host defense mechanism are discussed. Full article
(This article belongs to the Special Issue Antiviral Responses to Herpes Viruses)
Open AccessReview Antibody-Mediated Fcγ Receptor-Based Mechanisms of HIV Inhibition: Recent Findings and New Vaccination Strategies
Viruses 2009, 1(3), 1265-1294; doi:10.3390/v1031265
Received: 30 September 2009 / Revised: 1 December 2009 / Accepted: 8 December 2009 / Published: 15 December 2009
Cited by 15 | PDF Full-text (295 KB) | HTML Full-text | XML Full-text
Abstract
The HIV/AIDS pandemic is one of the most devastating pandemics worldwide. Today, the major route of infection by HIV is sexual transmission. One of the most promising strategies for vaccination against HIV sexual infection is the development of a mucosal vaccine, which should
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The HIV/AIDS pandemic is one of the most devastating pandemics worldwide. Today, the major route of infection by HIV is sexual transmission. One of the most promising strategies for vaccination against HIV sexual infection is the development of a mucosal vaccine, which should be able to induce strong local and systemic protective immunity. It is believed that both humoral and cellular immune responses are needed for inducing a sterilizing protection against HIV. Recently, passive administration of monoclonal neutralizing antibodies in macaques infected by vaginal challenge demonstrated a crucial role of FcγRs in the protection afforded by these antibodies. This questioned about the role of innate and adaptive immune functions, including ADCC, ADCVI, phagocytosis of opsonized HIV particles and the production of inflammatory cytokines and chemokines, in the mechanism of HIV inhibition in vivo. Other monoclonal antibodies - non-neutralizing inhibitory antibodies - which recognize immunogenic epitopes, have been shown to display potent FcγRs-dependent inhibition of HIV replication in vitro. The potential role of these antibodies in protection against sexual transmission of HIV and their biological relevance for the development of an HIV vaccine therefore need to be determined. This review highlights the potential role of FcγRsmediated innate and adaptive immune functions in the mechanism of HIV protection. Full article
(This article belongs to the Special Issue AIDS Vaccine)
Open AccessReview Viral Hybrid Vectors for Somatic Integration - Are They the Better Solution?
Viruses 2009, 1(3), 1295-1324; doi:10.3390/v1031295
Received: 30 September 2009 / Revised: 4 December 2009 / Accepted: 10 December 2009 / Published: 15 December 2009
Cited by 9 | PDF Full-text (660 KB) | HTML Full-text | XML Full-text
Abstract
The turbulent history of clinical trials in viral gene therapy has taught us important lessons about vector design and safety issues. Much effort was spent on analyzing genotoxicity after somatic integration of therapeutic DNA into the host genome. Based on these findings major
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The turbulent history of clinical trials in viral gene therapy has taught us important lessons about vector design and safety issues. Much effort was spent on analyzing genotoxicity after somatic integration of therapeutic DNA into the host genome. Based on these findings major improvements in vector design including the development of viral hybrid vectors for somatic integration have been achieved. This review provides a state-of-the-art overview of available hybrid vectors utilizing viruses for high transduction efficiencies in concert with various integration machineries for random and targeted integration patterns. It discusses advantages but also limitations of each vector system. Full article
(This article belongs to the Special Issue Novel Viral Vector Systems for Gene Therapy)
Open AccessReview Satellite RNAs and Satellite Viruses of Plants
Viruses 2009, 1(3), 1325-1350; doi:10.3390/v1031325
Received: 28 October 2009 / Revised: 7 December 2009 / Accepted: 7 December 2009 / Published: 18 December 2009
Cited by 39 | PDF Full-text (214 KB) | HTML Full-text | XML Full-text
Abstract
The view that satellite RNAs (satRNAs) and satellite viruses are purely molecular parasites of their cognate helper viruses has changed. The molecular mechanisms underlying the synergistic and/or antagonistic interactions among satRNAs/satellite viruses, helper viruses, and host plants are beginning to be comprehended. This
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The view that satellite RNAs (satRNAs) and satellite viruses are purely molecular parasites of their cognate helper viruses has changed. The molecular mechanisms underlying the synergistic and/or antagonistic interactions among satRNAs/satellite viruses, helper viruses, and host plants are beginning to be comprehended. This review aims to summarize the recent achievements in basic and practical research, with special emphasis on the involvement of RNA silencing mechanisms in the pathogenicity, population dynamics, and, possibly, the origin(s) of these subviral agents. With further research following current trends, the comprehensive understanding of satRNAs and satellite viruses could lead to new insights into the trilateral interactions among host plants, viruses, and satellites. Full article
(This article belongs to the Special Issue Subviral RNAs)
Open AccessReview H5N1 Virus Evolution in Europe—An Updated Overview
Viruses 2009, 1(3), 1351-1363; doi:10.3390/v1031351
Received: 18 September 2009 / Revised: 28 November 2009 / Accepted: 18 December 2009 / Published: 23 December 2009
Cited by 14 | PDF Full-text (185 KB) | HTML Full-text | XML Full-text
Abstract
Since its emergence in South East Asia in 2003, Highly Pathogenic Avian Influenza (HPAI) A/H5N1 has reportedly caused outbreaks in poultry and/or wild birds in 62 countries, of which 24 were in Europe. Interestingly, out of the many genetic clades circulating in Asia,
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Since its emergence in South East Asia in 2003, Highly Pathogenic Avian Influenza (HPAI) A/H5N1 has reportedly caused outbreaks in poultry and/or wild birds in 62 countries, of which 24 were in Europe. Interestingly, out of the many genetic clades circulating in Asia, the westward spread of HPAI A/H5N1 to Central Asia, the Middle East, Europe and Africa was dominated by one single clade, namely clade 2.2. In this paper, we review and update through phylogenetic and gene migrational analysis the information concerning the evolution and the molecular epidemiology of HPAI A/H5N1 on the European continent. Full article
(This article belongs to the Special Issue Influenza: Pandemics and Vaccinations)

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