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Search Results: 1 - 10 of 210052 matches for " Norman L. Letvin "
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Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys
Ina Hellmann,So-Yon Lim,Rebecca S. Gelman,Norman L. Letvin
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002436
Abstract: While the contribution of CD8+ cytotoxic T lymphocytes to early containment of HIV-1 spread is well established, a role for NK cells in controlling HIV-1 replication during primary infection has been uncertain. The highly polymorphic family of KIR molecules expressed on NK cells can inhibit or activate these effector cells and might therefore modulate their activity against HIV-1-infected cells. In the present study, we investigated copy number variation in KIR3DH loci encoding the only activating KIR receptor family in rhesus monkeys and its effect on simian immunodeficiency virus (SIV) replication during primary infection in rhesus monkeys. We observed an association between copy numbers of KIR3DH genes and control of SIV replication in Mamu-A*01– rhesus monkeys that express restrictive TRIM5 alleles. These findings provide further evidence for an association between NK cells and the early containment of SIV replication, and underscore the potential importance of activating KIRs in stimulating NK cell responses to control SIV spread.
Coping with Viral Diversity in HIV Vaccine Design: A Response to Nickle et al.
Will Fischer,H. X Liao,Barton F Haynes,Norman L Letvin,Bette Korber
PLOS Computational Biology , 2008, DOI: 10.1371/journal.pcbi.0040015
Variability in a dominant block to SIV early reverse transcription in rhesus monkey cells predicts in vivo viral replication and time to death
Thomas F Rogers, So-Yon Lim, TJ Sundsvold, Tiffany Chan, Ariel Hsu, Norman L Letvin
Virology Journal , 2010, DOI: 10.1186/1743-422x-7-79
Abstract: Humans vary in their susceptibility to human immunodeficiency virus type 1 (HIV-1) acquisition and in the level of HIV-1 replication following infection [1,2]. Virus phenotype, the magnitude of cytotoxic T lymphocyte response, major histocompatability complex (MHC) class I haplotype, and chemokine receptor polymorphisms have all been shown to contribute to this variability [3-5]. Recent studies suggest that further undefined host factors are also contributing to the level of virus control in the HIV-1-infected individual [6].Some of the undefined host factors contributing to HIV-1 containment may be responsible for the variable ability of cells to be infected by and sustain replication of these viruses. It has been shown that permissiveness for HIV-1 varies substantially between isolated primary cells Permissiveness, the ability of cells to be infected and sustain the replication of HIV-1, also varies substantially between isolated primary cells of individuals [7]. It has been shown that the permissiveness of isolated primary rhesus monkey lymphocytes for SIV infection correlates with in vivo viral set point [8].The variability in permissiveness observed in rhesus monkey PBMC for SIV replication can be shaped by dominant and nondominant mechanisms: through the altered expression of required host factors and/or virus restricting molecules [9]. The ability of a cell to become infected by HIV/SIV requires cellular expression of diverse proteins and HIV/SIV replication can be repressed by the cellular expression of a number of restriction factors including TRIM5α and APOBEC3G [10,11]. While the restriction factor TRIM5α appears to be under positive selection and is highly polymorphic in a given species, there is little evidence that this genetic variability has functional consequences [12-15].We set out to identify genetic mechanisms underlying the variable susceptibility to lentivirus replication in a primate species through an analysis of the differential rhesus monke
In Vivo Anti-HIV Activity of the Heparin-Activated Serine Protease Inhibitor Antithrombin III Encapsulated in Lymph-Targeting Immunoliposomes
Mohammed Asmal, James B. Whitney, Corinne Luedemann, Angela Carville, Robert Steen, Norman L. Letvin, Ralf Geiben-Lynn
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048234
Abstract: Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log10 reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention.
TRIM5α Modulates Immunodeficiency Virus Control in Rhesus Monkeys
So-Yon Lim,Thomas Rogers,Tiffany Chan,James B. Whitney,Jonghwa Kim,Joseph Sodroski,Norman L. Letvin
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000738
Abstract: The cytoplasmic TRIM5α proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5α proteins of the natural hosts. To address whether TRIM5α contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5α cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5α B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys to SIVmac infection. We also show the importance in vivo of the interaction of SIVmac with different allelic forms of TRIM5, demonstrating that particular alleles are associated with as much as 1.3 median log difference in set-point viral loads in SIVmac-infected rhesus monkeys. Moreover, these allelic forms of TRIM5 were associated with the extent of loss of central memory (CM) CD4+ T cells and the rate of progression to AIDS in the infected monkeys. These findings demonstrate a central role for TRIM5α in limiting the replication of an immunodeficiency virus infection in a primate host.
Contributions of Mamu-A*01 Status and TRIM5 Allele Expression, But Not CCL3L Copy Number Variation, to the Control of SIVmac251 Replication in Indian-Origin Rhesus Monkeys
So-Yon Lim,Tiffany Chan,Rebecca S. Gelman,James B. Whitney,Kara L. O'Brien,Dan H. Barouch,David B. Goldstein,Barton F. Haynes,Norman L. Letvin
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000997
Abstract: CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis.
Thy1+ Nk Cells from Vaccinia Virus-Primed Mice Confer Protection against Vaccinia Virus Challenge in the Absence of Adaptive Lymphocytes
Geoffrey O. Gillard,Maytal Bivas-Benita,Avi-Hai Hovav,Lauren E. Grandpre,Michael W. Panas,Michael S. Seaman,Barton F. Haynes,Norman L. Letvin
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002141
Abstract: While immunological memory has long been considered the province of T- and B- lymphocytes, it has recently been reported that innate cell populations are capable of mediating memory responses. We now show that an innate memory immune response is generated in mice following infection with vaccinia virus, a poxvirus for which no cognate germline-encoded receptor has been identified. This immune response results in viral clearance in the absence of classical adaptive T and B lymphocyte populations, and is mediated by a Thy1+ subset of natural killer (NK) cells. We demonstrate that immune protection against infection from a lethal dose of virus can be adoptively transferred with memory hepatic Thy1+ NK cells that were primed with live virus. Our results also indicate that, like classical immunological memory, stronger innate memory responses form in response to priming with live virus than a highly attenuated vector. These results demonstrate that a defined innate memory cell population alone can provide host protection against a lethal systemic infection through viral clearance.
Local replication of simian immunodeficiency virus in the breast milk compartment of chronically-infected, lactating rhesus monkeys
Sallie R Permar, Helen H Kang, Andrew B Wilks, Linh V Mach, Angela Carville, Keith G Mansfield, Gerald H Learn, Beatrice H Hahn, Norman L Letvin
Retrovirology , 2010, DOI: 10.1186/1742-4690-7-7
Abstract: While transmission via breastfeeding remains a significant mode of infant HIV acquisition, the mechanisms of this transmission are not well understood. The level of both cell-free and cell-associated virus in milk have been linked to the risk of HIV infection of breastfeeding infants [1-3]. Therefore, viral variants in the milk are a likely source of transmitted virus.Recent studies suggest that mucosal compartments are distinct from systemic compartments in their HIV/SIV-specific immune responses and virus quasispecies [4-8]. The immune response in milk may shape compartment-specific virus, as seen in other anatomic compartments such as semen and cervicovaginal fluid [6,9-11]. One study of the genetic diversity of milk virus suggested a difference in the dominant virus species in milk and peripheral blood [4]. A second study subsequently reported that the predominant virus in blood and milk were genetically similar, suggesting an equilibrium of virus between these compartments [12]. Thus, the production site of the virus transmitted via breastfeeding and the selection pressures that shape its genetic composition are not well understood.It is well established that HIV/SIV-specific cellular immune responses are critical for control of systemic virus replication [13] and progression to AIDS [14]. While HIV/SIV-specific cellular immune responses have been identified in milk [15,16], the role of these responses in containing local virus replication is unknown. Immunodominant cytotoxic T lymphocyte (CTL) epitopes of SIV and HIV are under significant cellular immune pressure, leading to distinct mutations within these epitopes that facilitate virus escape from CTL recognition. Therefore, the rate at which these CTL escape mutations occur within a virus population may be indicative of the magnitude of the cellular immune pressure in that compartment. However, rates of CTL escape of mucosal and systemic virus quasispecies have not previously been compared. As the proportion
TCR Affinity Associated with Functional Differences between Dominant and Subdominant SIV Epitope-Specific CD8+ T Cells in Mamu-A*01+ Rhesus Monkeys
Christa E. Osuna ,Ana Maria Gonzalez,Hsun-Hsien Chang,Amy Shi Hung,Elizabeth Ehlinger,Kara Anasti,S. Munir Alam,Norman L. Letvin
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004069
Abstract: Many of the factors that contribute to CD8+ T cell immunodominance hierarchies during viral infection are known. However, the functional differences that exist between dominant and subdominant epitope-specific CD8+ T cells remain poorly understood. In this study, we characterized the phenotypic and functional differences between dominant and subdominant simian immunodeficiency virus (SIV) epitope-specific CD8+ T cells restricted by the major histocompatibility complex (MHC) class I allele Mamu-A*01 during acute and chronic SIV infection. Whole genome expression analyses during acute infection revealed that dominant SIV epitope-specific CD8+ T cells had a gene expression profile consistent with greater maturity and higher cytotoxic potential than subdominant epitope-specific CD8+ T cells. Flow-cytometric measurements of protein expression and anti-viral functionality during chronic infection confirmed these phenotypic and functional differences. Expression analyses of exhaustion-associated genes indicated that LAG-3 and CTLA-4 were more highly expressed in the dominant epitope-specific cells during acute SIV infection. Interestingly, only LAG-3 expression remained high during chronic infection in dominant epitope-specific cells. We also explored the binding interaction between peptide:MHC (pMHC) complexes and their cognate TCRs to determine their role in the establishment of immunodominance hierarchies. We found that epitope dominance was associated with higher TCR:pMHC affinity. These studies demonstrate that significant functional differences exist between dominant and subdominant epitope-specific CD8+ T cells within MHC-restricted immunodominance hierarchies and suggest that TCR:pMHC affinity may play an important role in determining the frequency and functionality of these cell populations. These findings advance our understanding of the regulation of T cell immunodominance and will aid HIV vaccine design.
Genital Tract Sequestration of SIV following Acute Infection
James B. Whitney ,Peter T. Hraber,Corinne Luedemann,Elena E. Giorgi,Marcus G. Daniels,Tanmoy Bhattacharya,Srinivas S. Rao,John R. Mascola,Gary J. Nabel,Bette T. Korber,Norman L. Letvin
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1001293
Abstract: We characterized the evolution of simian immunodeficiency virus (SIV) in the male genital tract by examining blood- and semen-associated virus from experimentally and sham vaccinated rhesus monkeys during primary infection. At the time of peak virus replication, SIV sequences were intermixed between the blood and semen supporting a scenario of high-level virus “spillover” into the male genital tract. However, at the time of virus set point, compartmentalization was apparent in 4 of 7 evaluated monkeys, likely as a consequence of restricted virus gene flow between anatomic compartments after the resolution of primary viremia. These findings suggest that SIV replication in the male genital tract evolves to compartmentalization after peak viremia resolves.
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