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Search Results: 1 - 10 of 408306 matches for " Steven M. Wolinsky "
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Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses
Shetal Arjan-Odedra, Chad M Swanson, Nathan M Sherer, Steven M Wolinsky, Michael H Malim
Retrovirology , 2012, DOI: 10.1186/1742-4690-9-53
Abstract: MOV10 overexpression substantially decreased the production of infectious retrovirus particles, as well the propagation of LTR and non-LTR endogenous retroelements. Most significantly, RNAi-mediated silencing of endogenous MOV10 enhanced the replication of both LTR and non-LTR endogenous retroelements, but not the production of infectious retrovirus particles demonstrating that natural levels of MOV10 suppress retrotransposition, but have no impact on infection by exogenous retroviruses. Furthermore, functional studies showed that MOV10 is not necessary for miRNA or siRNA-mediated mRNA silencing.We have identified novel specificity for human MOV10 in the control of retroelement replication and hypothesise that MOV10 may be a component of a cellular pathway or process that selectively regulates the replication of endogenous retroelements in somatic cells.
APOBEC3G Inhibits Elongation of HIV-1 Reverse Transcripts
Kate N. Bishop,Mohit Verma,Eun-Young Kim,Steven M. Wolinsky,Michael H. Malim
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000231
Abstract: APOBEC3G (A3G) is a host cytidine deaminase that, in the absence of Vif, restricts HIV-1 replication and reduces the amount of viral DNA that accumulates in cells. Initial studies determined that A3G induces extensive mutation of nascent HIV-1 cDNA during reverse transcription. It has been proposed that this triggers the degradation of the viral DNA, but there is now mounting evidence that this mechanism may not be correct. Here, we use a natural endogenous reverse transcriptase assay to show that, in cell-free virus particles, A3G is able to inhibit HIV-1 cDNA accumulation not only in the absence of hypermutation but also without the apparent need for any target cell factors. We find that although reverse transcription initiates in the presence of A3G, elongation of the cDNA product is impeded. These data support the model that A3G reduces HIV-1 cDNA levels by inhibiting synthesis rather than by inducing degradation.
Preservation of Tetherin and CD4 Counter-Activities in Circulating Vpu Alleles despite Extensive Sequence Variation within HIV-1 Infected Individuals
Suzanne Pickering,Stephane Hué,Eun-Young Kim,Susheel Reddy,Steven M. Wolinsky,Stuart J. D. Neil
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003895
Abstract: The HIV-1 Vpu protein is expressed from a bi-cistronic message late in the viral life cycle. It functions during viral assembly to maximise infectious virus release by targeting CD4 for proteosomal degradation and counteracting the antiviral protein tetherin (BST2/CD317). Single genome analysis of vpu repertoires throughout infection in 14 individuals infected with HIV-1 clade B revealed extensive amino acid diversity of the Vpu protein. For the most part, this variation in Vpu increases over the course of infection and is associated with predicted epitopes of the individual's MHC class I haplotype, suggesting CD8+ T cell pressure is the major driver of Vpu sequence diversity within the host. Despite this variability, the Vpu functions of targeting CD4 and counteracting both physical virus restriction and NF-κB activation by tetherin are rigorously maintained throughout HIV-1 infection. Only a minority of circulating alleles bear lesions in either of these activities at any given time, suggesting functional Vpu mutants are heavily selected against even at later stages of infection. Comparison of Vpu proteins defective for one or several functions reveals novel determinants of CD4 downregulation, counteraction of tetherin restriction, and inhibition of NF-κB signalling. These data affirm the importance of Vpu functions for in vivo persistence of HIV-1 within infected individuals, not simply for transmission, and highlight its potential as a target for antiviral therapy.
Differential MHC class I expression in distinct leukocyte subsets
Justin M Greene, Roger W Wiseman, Simon M Lank, Benjamin N Bimber, Julie A Karl, Benjamin J Burwitz, Jennifer J Lhost, Oriana E Hawkins, Kevin J Kunstman, Karl W Broman, Steven M Wolinsky, William H Hildebrand, David H O'Connor
BMC Immunology , 2011, DOI: 10.1186/1471-2172-12-39
Abstract: We examined MHC gene expression in human and macaque leukocyte subsets. In humans, while we detected overall differences in locus transcription, we found that transcription of MHC class I genes was consistent across the leukocyte subsets we studied with only small differences detected. In contrast, transcription of certain MHC cDNA species in macaques varied dramatically by up to 45% between different subsets. Although the Mafa-B*134:02 RNA is virtually undetectable in CD4+ T cells, it represents over 45% of class I transcripts in CD14+ monocytes. We observed parallel MHC transcription differences in rhesus macaques. Finally, we analyzed expression of select MHC proteins at the cell surface using fluorescent peptides. This technique confirmed results from the transcriptional analysis and demonstrated that other MHC proteins, known to restrict SIV-specific responses, are also differentially expressed among distinct leukocyte subsets.We assessed MHC class I transcription and expression in human and macaque leukocyte subsets. Until now, it has been difficult to examine MHC class I allele expression due to the similarity of MHC class I sequences. Using two novel techniques we showed that expression varies among distinct leukocyte subsets of macaques but does not vary dramatically in the human cell subsets we examined. These findings suggest pathogen tropism may have a profound impact on the shape and focus of the MHC class I restricted CD8+ T cell response in macaques.MHC class I genes are critical to the development of the cellular immune response. The products of these genes are cell surface glycoproteins expressed on nearly every nucleated cell. These molecules present short fragments of endogenous proteins to surveillance CD8+ T cells. Once a cell becomes cancerous or is infiltrated by an intracellular pathogen, MHC class I proteins present these foreign peptide fragments to CD8+ T cells. CD8+ T cells can secrete cytokines and kill cells presenting specific MHC-anti
SHIV-162P3 Infection of Rhesus Macaques Given Maraviroc Gel Vaginally Does Not Involve Resistant Viruses
Athe M. N. Tsibris, Urboshi Pal, Allison L. Schure, Ronald S. Veazey, Kevin J. Kunstman, Timothy J. Henrich, P. J. Klasse, Steven M. Wolinsky, Daniel R. Kuritzkes, John P. Moore
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028047
Abstract: Maraviroc (MVC) gels are effective at protecting rhesus macaques from vaginal SHIV transmission, but breakthrough infections can occur. To determine the effects of a vaginal MVC gel on infecting SHIV populations in a macaque model, we analyzed plasma samples from three rhesus macaques that received a MVC vaginal gel (day 0) but became infected after high-dose SHIV-162P3 vaginal challenge. Two infected macaques that received a placebo gel served as controls. The infecting SHIV-162P3 stock had an overall mean genetic distance of 0.294±0.027%; limited entropy changes were noted across the envelope (gp160). No envelope mutations were observed consistently in viruses isolated from infected macaques at days 14–21, the time of first detectable viremia, nor selected at later time points, days 42–70. No statistically significant differences in MVC susceptibilities were observed between the SHIV inoculum (50% inhibitory concentration [IC50] 1.87 nM) and virus isolated from the three MVC-treated macaques (MVC IC50 1.18 nM, 1.69 nM, and 1.53 nM, respectively). Highlighter plot analyses suggested that infection was established in each MVC-treated animal by one founder virus genotype. The expected Poisson distribution of pairwise Hamming Distance frequency counts was observed and a phylogenetic analysis did not identify infections with distinct lineages from the challenge stock. These data suggest that breakthrough infections most likely result from incomplete viral inhibition and not the selection of MVC-resistant variants.
Microbial Translocation Is Associated with Increased Monocyte Activation and Dementia in AIDS Patients
Petronela Ancuta, Anupa Kamat, Kevin J. Kunstman, Eun-Young Kim, Patrick Autissier, Alysse Wurcel, Tauheed Zaman, David Stone, Megan Mefford, Susan Morgello, Elyse J. Singer, Steven M. Wolinsky, Dana Gabuzda
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002516
Abstract: Elevated plasma lipopolysaccharide (LPS), an indicator of microbial translocation from the gut, is a likely cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation and trafficking into brain, which are key mechanisms in the pathogenesis of HIV-associated dementia (HAD). To determine whether high LPS levels are associated with increased monocyte activation and HAD, we obtained peripheral blood samples from AIDS patients and examined plasma LPS by Limulus amebocyte lysate (LAL) assay, peripheral blood monocytes by FACS, and soluble markers of monocyte activation by ELISA. Purified monocytes were isolated by FACS sorting, and HIV DNA and RNA levels were quantified by real time PCR. Circulating monocytes expressed high levels of the activation markers CD69 and HLA-DR, and harbored low levels of HIV compared to CD4+ T-cells. High plasma LPS levels were associated with increased plasma sCD14 and LPS-binding protein (LBP) levels, and low endotoxin core antibody levels. LPS levels were higher in HAD patients compared to control groups, and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using intravenous heroin and/or ethanol, or with Hepatitis C virus (HCV) co-infection, compared to control groups. These results suggest a role for elevated LPS levels in driving monocyte activation in AIDS, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse and HCV co-infection influence these processes.
Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection
Eun-Young Kim,Ramon Lorenzo-Redondo,Susan J. Little,Yoon-Seok Chung,Prabhjeet K. Phalora,Irina Maljkovic Berry,John Archer,Sudhir Penugonda,Will Fischer,Douglas D. Richman,Tanmoy Bhattacharya,Michael H. Malim ,Steven M. Wolinsky
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004281
Abstract: Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1) cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.
Copy Number Variation of KIR Genes Influences HIV-1 Control
Kimberly Pelak,Anna C. Need,Jacques Fellay,Kevin V. Shianna,Sheng Feng,Thomas J. Urban,Dongliang Ge,Andrea De Luca,Javier Martinez-Picado,Steven M. Wolinsky,Jeremy J. Martinson,Beth D. Jamieson,Jay H. Bream,Maureen P. Martin,Persephone Borrow,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Amalio Telenti,Mary Carrington,David B. Goldstein,Galit Alter
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001208
Abstract: A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.
Copy Number Variation of KIR Genes Influences HIV-1 Control
Kimberly Pelak equal contributor,Anna C. Need equal contributor,Jacques Fellay equal contributor,Kevin V. Shianna,Sheng Feng,Thomas J. Urban,Dongliang Ge,Andrea De Luca,Javier Martinez-Picado,Steven M. Wolinsky,Jeremy J. Martinson,Beth D. Jamieson,Jay H. Bream,Maureen P. Martin,Persephone Borrow,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Amalio Telenti,Mary Carrington,David B. Goldstein,Galit Alter ,on behalf of NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001208
Abstract: A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.
HLA and HIV Infection Progression: Application of the Minimum Description Length Principle to Statistical Genetics
Peter T. Hraber,Bette T. Korber,Steven Wolinsky,Henry A. Erlich,Elizabeth A. Trachtenberg,Thomas B. Kepler
Mathematics , 2005, DOI: 10.1007/11946465_1
Abstract: The minimum description length (MDL) principle states that the best model to account for some data minimizes the sum of the lengths, in bits, of the descriptions of the model and the residual error. The description length is thus a criterion for model selection. Description-length analysis of HLA alleles from the Chicago MACS cohort enables classification of alleles associated with plasma HIV RNA, an indicator of infection progression. Progression variation is most strongly associated with HLA-B. Individuals without B58s supertype alleles average viral RNA levels 3.6-fold greater than individuals with them.
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