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Viruses, Volume 3, Issue 5 (May 2011), Pages 423-619

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Research

Jump to: Review, Other

Open AccessArticle Susceptibility of Primary HTLV-1 Isolates from Patients with HTLV-1-Associated Myelopathy to Reverse Transcriptase Inhibitors
Viruses 2011, 3(5), 469-483; doi:10.3390/v3050469
Received: 25 February 2011 / Revised: 6 April 2011 / Accepted: 21 April 2011 / Published: 5 May 2011
Cited by 15 | PDF Full-text (308 KB)
Abstract
Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo [...] Read more.
Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo results have been disappointing. We therefore assayed the sensitivity of HTLV-1 primary isolates to a panel of RT inhibitors. HTLV-1 primary isolates were obtained, pre- and post- NRTI treatment, from patients with HTLV-1-associated myelopathy. Sensitivity to azidothymidine (AZT), lamivudine (3TC), tenofovir (TDF) and three phosphonated carbocyclic 2’-oxa-3’aza nucleosides (PCOANs) was assessed in a RT inhibitor assay. With the exception of 3TC, HTLV RT from primary isolates was less sensitive to all tested inhibitors than HTLV-1 RT from MT-2 cells. HTLV-1 RT from primary isolates and from chronically infected, transformed MT-2 cells was insensitive to 3TC. Sensitivity of primary isolates to RT inhibitors was not reduced following up to 12 months of patient treatment with AZT plus 3TC. The sensitivity of HTLV-1 primary isolates to NRTIs differs from that of cell lines and may vary among patients. Failure of NRTIs to reduce HTLV-1 viral load in vivo was not due to the development of phenotypic NRTI resistance. AZT and the three PCOANs assayed all consistently inhibited primary isolate HTLV-1 RT. Full article
(This article belongs to the Special Issue Recent Developments in HTLV Research)

Review

Jump to: Research, Other

Open AccessReview Retroviral Vectors: Post Entry Events and Genomic Alterations
Viruses 2011, 3(5), 429-455; doi:10.3390/v3050429
Received: 9 February 2011 / Revised: 24 March 2011 / Accepted: 5 April 2011 / Published: 29 April 2011
Cited by 14 | PDF Full-text (687 KB)
Abstract
The curative potential of retroviral vectors for somatic gene therapy has been demonstrated impressively in several clinical trials leading to sustained long-term correction of the underlying genetic defect. Preclinical studies and clinical monitoring of gene modified hematopoietic stem and progenitor cells in [...] Read more.
The curative potential of retroviral vectors for somatic gene therapy has been demonstrated impressively in several clinical trials leading to sustained long-term correction of the underlying genetic defect. Preclinical studies and clinical monitoring of gene modified hematopoietic stem and progenitor cells in patients have shown that biologically relevant vector induced side effects, ranging from in vitro immortalization to clonal dominance and oncogenesis in vivo, accompany therapeutic efficiency of integrating retroviral gene transfer systems. Most importantly, it has been demonstrated that the genotoxic potential is not identical among all retroviral vector systems designed for clinical application. Large scale viral integration site determination has uncovered significant differences in the target site selection of retrovirus subfamilies influencing the propensity for inducing genetic alterations in the host genome. In this review we will summarize recent insights gained on the mechanisms of insertional mutagenesis based on intrinsic target site selection of different retrovirus families. We will also discuss examples of side effects occurring in ongoing human gene therapy trials and future prospectives in the field. Full article
(This article belongs to the Special Issue Retroviral Vectors)
Open AccessReview Making Sense out of Antisense Transcription in Human T-Cell Lymphotropic Viruses (HTLVs)
Viruses 2011, 3(5), 456-468; doi:10.3390/v3050456
Received: 9 March 2011 / Revised: 14 April 2011 / Accepted: 15 April 2011 / Published: 5 May 2011
Cited by 19 | PDF Full-text (229 KB)
Abstract
Retroviral gene expression generally depends on a full-length transcript that initiates in the 5' long terminal repeat (LTR), which is either unspliced or alternatively spliced. We and others have demonstrated the existence of an antisense transcript initiating in the 3' LTR of [...] Read more.
Retroviral gene expression generally depends on a full-length transcript that initiates in the 5' long terminal repeat (LTR), which is either unspliced or alternatively spliced. We and others have demonstrated the existence of an antisense transcript initiating in the 3' LTR of the Human T-cell Leukemia Virus type 1 (HTLV-1) that is involved in the production of HBZ (HTLV-1 basic leucine zipper (bZIP) factor). HBZ is a Fos-like factor capable of inhibiting Tax-mediated activation of the HTLV-1 LTR by interacting with the cellular transcription factor cAMP-response element-binding protein (CREB) and the pleiotropic cellular coactivators p300/CBP. HBZ can also activate cellular transcription through its interaction with p300/CBP. Interestingly, HBZ has also been found to promote T-lymphocyte proliferation. By down-regulating viral expression and by stimulating T-cell proliferation, HBZ could be essential in the establishment of a chronic infection. Antisense transcription also occurs in the closely related HTLV-2 retrovirus as well as in the recently discovered HTLV-3 and HTLV-4. These antisense transcripts are also involved in the production of retroviral proteins that we have termed Antisense Protein of HTLVs (APH). Like HBZ, the APH proteins are localized in the nucleus of transfected cells and repress Tax-mediated viral transcription. Full article
(This article belongs to the Special Issue Recent Developments in HTLV Research)
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Open AccessReview The Pathogenesis of Rift Valley Fever
Viruses 2011, 3(5), 493-519; doi:10.3390/v3050493
Received: 31 March 2011 / Revised: 26 April 2011 / Accepted: 2 May 2011 / Published: 6 May 2011
Cited by 72 | PDF Full-text (421 KB)
Abstract
Rift Valley fever (RVF) is an emerging zoonotic disease distributed in sub-Saharan African countries and the Arabian Peninsula. The disease is caused by the Rift Valley fever virus (RVFV) of the family Bunyaviridae and the genus Phlebovirus. The virus is transmitted [...] Read more.
Rift Valley fever (RVF) is an emerging zoonotic disease distributed in sub-Saharan African countries and the Arabian Peninsula. The disease is caused by the Rift Valley fever virus (RVFV) of the family Bunyaviridae and the genus Phlebovirus. The virus is transmitted by mosquitoes, and virus replication in domestic ruminant results in high rates of mortality and abortion. RVFV infection in humans usually causes a self-limiting, acute and febrile illness; however, a small number of cases progress to neurological disorders, partial or complete blindness, hemorrhagic fever, or thrombosis. This review describes the pathology of RVF in human patients and several animal models, and summarizes the role of viral virulence factors and host factors that affect RVFV pathogenesis. Full article
(This article belongs to the Special Issue Pathogenesis of Emerging and Re-Emerging RNA Viruses)
Open AccessReview Antiviral Inhibition of Enveloped Virus Release by Tetherin/BST-2: Action and Counteraction
Viruses 2011, 3(5), 520-540; doi:10.3390/v3050520
Received: 18 March 2011 / Revised: 19 April 2011 / Accepted: 28 April 2011 / Published: 6 May 2011
Cited by 34 | PDF Full-text (596 KB)
Abstract
Tetherin (BST2/CD317) has been recently recognized as a potent interferon-induced antiviral molecule that inhibits the release of diverse mammalian enveloped virus particles from infected cells. By targeting an immutable structure common to all these viruses, the virion membrane, evasion of this antiviral [...] Read more.
Tetherin (BST2/CD317) has been recently recognized as a potent interferon-induced antiviral molecule that inhibits the release of diverse mammalian enveloped virus particles from infected cells. By targeting an immutable structure common to all these viruses, the virion membrane, evasion of this antiviral mechanism has necessitated the development of specific countermeasures that directly inhibit tetherin activity. Here we review our current understanding of the molecular basis of tetherin’s mode of action, the viral countermeasures that antagonize it, and how virus/tetherin interactions may affect viral transmission and pathogenicity. Full article
(This article belongs to the Special Issue Antiviral Innate Immunity)
Open AccessReview Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences
Viruses 2011, 3(5), 541-560; doi:10.3390/v3050541
Received: 26 March 2011 / Accepted: 26 April 2011 / Published: 9 May 2011
Cited by 18 | PDF Full-text (586 KB)
Abstract
Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene [...] Read more.
Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity. Full article
(This article belongs to the Special Issue Recent Developments in HTLV Research)
Open AccessReview Foamy Virus Biology and Its Application for Vector Development
Viruses 2011, 3(5), 561-585; doi:10.3390/v3050561
Received: 7 March 2011 / Revised: 21 April 2011 / Accepted: 23 April 2011 / Published: 11 May 2011
Cited by 38 | PDF Full-text (750 KB) | HTML Full-text | XML Full-text
Abstract
Spuma- or foamy viruses (FV), endemic in most non-human primates, cats, cattle and horses, comprise a special type of retrovirus that has developed a replication strategy combining features of both retroviruses and hepadnaviruses. Unique features of FVs include an apparent apathogenicity in [...] Read more.
Spuma- or foamy viruses (FV), endemic in most non-human primates, cats, cattle and horses, comprise a special type of retrovirus that has developed a replication strategy combining features of both retroviruses and hepadnaviruses. Unique features of FVs include an apparent apathogenicity in natural hosts as well as zoonotically infected humans, a reverse transcription of the packaged viral RNA genome late during viral replication resulting in an infectious DNA genome in released FV particles and a special particle release strategy depending capsid and glycoprotein coexpression and specific interaction between both components. In addition, particular features with respect to the integration profile into the host genomic DNA discriminate FV from orthoretroviruses. It appears that some inherent properties of FV vectors set them favorably apart from orthoretroviral vectors and ask for additional basic research on the viruses as well as on the application in Gene Therapy. This review will summarize the current knowledge of FV biology and the development as a gene transfer system. Full article
(This article belongs to the Special Issue Retroviral Vectors)
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Open AccessReview CD4+ T Cell Depletion in Human Immunodeficiency Virus (HIV) Infection: Role of Apoptosis
Viruses 2011, 3(5), 586-612; doi:10.3390/v3050586
Received: 24 March 2011 / Revised: 3 May 2011 / Accepted: 4 May 2011 / Published: 12 May 2011
Cited by 29 | PDF Full-text (594 KB)
Abstract
Human immunodeficiency virus (HIV) infection is principally a mucosal disease and the gastrointestinal (GI) tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute [...] Read more.
Human immunodeficiency virus (HIV) infection is principally a mucosal disease and the gastrointestinal (GI) tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT) might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis. Full article

Other

Jump to: Research, Review

Open AccessCommentary Caging the Beast: TRIM5α Binding to the HIV-1 Core
Viruses 2011, 3(5), 423-428; doi:10.3390/v3050423
Received: 16 March 2011 / Revised: 21 April 2011 / Accepted: 21 April 2011 / Published: 27 April 2011
Cited by 11 | PDF Full-text (255 KB)
Abstract
The potent HIV-1 inhibitor TRIM5α blocks HIV-1 infection by accelerating the uncoating of HIV-1. TRIM5α is known to form higher-order self-association complexes that contribute to the avidity of TRIM5α for the HIV-1 capsid, and are essential to inhibit infection; these higher-order self-association [...] Read more.
The potent HIV-1 inhibitor TRIM5α blocks HIV-1 infection by accelerating the uncoating of HIV-1. TRIM5α is known to form higher-order self-association complexes that contribute to the avidity of TRIM5α for the HIV-1 capsid, and are essential to inhibit infection; these higher-order self-association complexes are dependent upon an intact B-box 2 domain. Even though the ability to form higher-order self-association complexes resembles the clathrin triskelion that forms a protein array, or cage, around the endocytic vesicle, evidence for the ability of TRIM5α to assemble a similar type of structure surrounding the HIV-1 core has been lacking. Recent work by Ganser-Pornillos, Chandrasekaran and colleagues has now demonstrated the ability of the restriction factor TRIM5α to “cage” or “net” the HIV-1 core by forming an hexagonal array on the surface of the viral capsid [1]. This hexagonal array is strikingly similar in design to the array formed by the clathrin triskelion on the surface of the clathrin-coated endocytic vesicle. This remarkable finding represents an important advance on our understanding of the restriction factor TRIM5α, and suggests that TRIM5α cages the HIV-1 core in order to terminate infection. The present note discusses the implications of this discovery. Full article
(This article belongs to the Section Editorial)
Open AccessCommentary A Long-Awaited Structure Is Rev-ealed
Viruses 2011, 3(5), 484-492; doi:10.3390/v3050484
Received: 16 March 2011 / Revised: 20 April 2011 / Accepted: 26 April 2011 / Published: 5 May 2011
Cited by 6 | PDF Full-text (392 KB)
Abstract
It has been known for some time that the HIV Rev protein binds and oligomerizes on a well-defined multiple stem-loop RNA structure, named the Rev Response Element (RRE), which is present in a subset of HIV mRNAs. This binding is the first [...] Read more.
It has been known for some time that the HIV Rev protein binds and oligomerizes on a well-defined multiple stem-loop RNA structure, named the Rev Response Element (RRE), which is present in a subset of HIV mRNAs. This binding is the first step in a pathway that overcomes a host restriction, which would otherwise prevent the export of these RNAs to the cytoplasm. Four recent publications now provide new insight into the structure of Rev and the multimeric RNA-protein complex that forms on the RRE [1–4]. Two unexpected and remarkable findings revealed in these studies are the flexibility of RNA binding that is demonstrated by the Rev arginine-rich RNA binding motif, and the way that both Rev protein and RRE contribute to the formation of the complex in a highly cooperative fashion. These studies also define the Rev dimerization and oligomerization interfaces to a resolution of 2.5Å, providing a framework necessary for further structural and functional studies. Additionally, and perhaps most importantly, they also pave the way for rational drug design, which may ultimately lead to new therapies to inhibit this essential HIV function. Full article
(This article belongs to the Section Editorial)
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Open AccessShort Note Meta-Analysis of High-Throughput Datasets Reveals Cellular Responses Following Hemorrhagic Fever Virus Infection
Viruses 2011, 3(5), 613-619; doi:10.3390/v3050613
Received: 2 April 2011 / Accepted: 20 April 2011 / Published: 12 May 2011
Cited by 5 | PDF Full-text (191 KB)
Abstract
The continuing use of high-throughput assays to investigate cellular responses to infection is providing a large repository of information. Due to the large number of differentially expressed transcripts, often running into the thousands, the majority of these data have not been thoroughly [...] Read more.
The continuing use of high-throughput assays to investigate cellular responses to infection is providing a large repository of information. Due to the large number of differentially expressed transcripts, often running into the thousands, the majority of these data have not been thoroughly investigated. Advances in techniques for the downstream analysis of high-throughput datasets are providing additional methods for the generation of additional hypotheses for further investigation. The large number of experimental observations, combined with databases that correlate particular genes and proteins with canonical pathways, functions and diseases, allows for the bioinformatic exploration of functional networks that may be implicated in replication or pathogenesis. Herein, we provide an example of how analysis of published high-throughput datasets of cellular responses to hemorrhagic fever virus infection can generate additional functional data. We describe enrichment of genes involved in metabolism, post-translational modification and cardiac damage; potential roles for specific transcription factors and a conserved involvement of a pathway based around cyclooxygenase-2. We believe that these types of analyses can provide virologists with additional hypotheses for continued investigation. Full article
(This article belongs to the Special Issue Pathogenesis of Emerging and Re-Emerging RNA Viruses)

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