Publications

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utility of human immunodeficiency virus type 1 envelope as a t-cell immunogen.human immunodeficiency virus (hiv)-specific cd8 t lymphocytes are important for the control of viremia, but the relative utility of responses to the various hiv proteins is controversial. immune responses that force escape mutations that exact a significant fitness cost from the mutating virus would help slow progression to aids. the hiv envelope (env) protein is subject to both humoral and cellular immune responses, suggesting that multiple rounds of mutation are needed to facilitate viral esca ...200717898063
changes in simian immunodeficiency virus reverse transcriptase alleles that appear during infection of macaques enhance infectivity and replication in cd4+ t cells.we previously showed that a slowly replicating, minimally pathogenic clone of simian immunodeficiency virus (siv), sivmnecl8, evolves increased ability to replicate in t cells with the onset of aids in pig-tailed macaques. moreover, molecular clones derived from late stages of infection (sivmne170 and sivmne027) replicate to high levels in vivo compared to sivmnecl8. here, we investigated the role of rt mutations in sivmne variant replication. we demonstrate selection for rt alleles that enhance ...200817904609
removal of a single n-linked glycan in human immunodeficiency virus type 1 gp120 results in an enhanced ability to induce neutralizing antibody responses.glycans on human immunodeficiency virus (hiv) envelope protein play an important role in infection and evasion from host immune responses. to examine the role of specific glycans, we introduced single or multiple mutations into potential n-linked glycosylation sites in hypervariable regions (v1 to v3) of the env gene of hiv type 1 (hiv-1) 89.6. three mutants tested showed enhanced sensitivity to soluble cd4. mutant n7 (n197q) in the carboxy-terminal stem of the v2 loop showed the most pronounced ...200817959660
characterization of plasmacytoid dendritic cells in bone marrow of pig-tailed macaques.plasmacytoid dendritic cells (pdcs), one of two types of bone marrow (bm)-derived blood dcs, play an important role in linking innate and adaptive immune responses. however, little is known about the nature of pdcs that reside in the bm. because the simian immunodeficiency virus-macaque model closely mimics human immunodeficiency virus disease in humans, with both infections inducing a decrease in pdcs, we characterized and compared pdcs in the bm with those in peripheral blood (pb) of healthy p ...200817989338
trimcyp expression in old world primates macaca nemestrina and macaca fascicularis.primates have evolved a variety of restriction factors that prevent retroviral replication. one such factor, trim5alpha, mediates a postentry restriction in many old world primates. among new world primates, aotus trivirgatus exerts a similar early restriction mediated by trimcyp, a trim5-cyclophilin a (cypa) chimera resulting from a cypa retrotransposition between exons 7 and 8 of the trim5 gene. macaca nemestrina do not express trim5alpha; therefore, we asked whether these animals and related ...200818287033
limited maintenance of vaccine-induced simian immunodeficiency virus-specific cd8 t-cell receptor clonotypes after virus challenge.t-cell receptors (tcrs) govern the specificity, efficacy, and cross-reactivity of cd8 t cells. here, we studied cd8 t-cell clonotypes from mane-a*10(+) pigtail macaques responding to the simian immunodeficiency virus (siv) gag kp9 epitope in a setting of vaccination and subsequent viral challenge. we observed a diverse tcr repertoire after dna, recombinant poxvirus, and live attenuated virus vaccination, with none of 59 vaccine-induced kp9-specific tcrs being identical between macaques. the kp9- ...200818508897
quantification of simian immunodeficiency virus cytotoxic t lymphocyte escape mutant viruses.escape from cytotoxic t-lymphocyte (ctl) pressure is common in hiv-1 infection of humans and simian immunodeficiency virus (siv) infections of macaques. ctl escape typically incurs a fitness cost as reversion back to wild-type can occur upon transmission. we utilized sequence-specific primers and dna probes with real-time polymerase chain reaction (pcr) to sensitively and specifically track wild-type and escape mutant viremia at the mane-a*17-restricted siv gag(371379) epitope af9 in pigtail mac ...200818620496
inactivated simian immunodeficiency virus-pulsed autologous fresh blood cells as an immunotherapy strategy.practical immunotherapies for human immunodeficiency virus infection are needed. we evaluated inactivated simian immunodeficiency virus (siv) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic siv(mac251) infection for t-cell immunogenicity in a randomized cross-over design study. the immunotherapy was safe and convincingly induced high levels of siv-specific cd4(+) t-cell responses (mean, 5.9% +/- 1.3% of all cd4(+) t cells) and to a lesser extent siv-speci ...200919019966
evaluation of recombinant influenza virus-simian immunodeficiency virus vaccines in macaques.there is an urgent need for human immunodeficiency virus (hiv) vaccines that induce robust mucosal immunity. influenza a viruses (both h1n1 and h3n2) were engineered to express simian immunodeficiency virus (siv) cd8 t-cell epitopes and evaluated following administration to the respiratory tracts of 11 pigtail macaques. influenza virus was readily detected from respiratory tract secretions, although the infections were asymptomatic. animals seroconverted to influenza virus and generated cd8 and ...200919439474
thrombocytopenia is strongly associated with simian aids in pigtail macaques.simian aids has a variable time course and presentation making it difficult to define disease effects of progressive simian immunodeficiency virus (siv) infection. we commonly observed thrombocytopenia (tcp) associated with progressive siv infection of pigtail macaques (macaca nemestrina). we therefore analyzed the relationship between platelet counts, viral load (vl), and cd4 t-cell levels in 44 unselected macaques with chronic siv infection. persistent tcp was observed in 70% of pigtail macaqu ...200919461525
a simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy.the treatment of human immunodeficiency virus type 1 (hiv-1) infection with highly active antiretroviral therapy (haart), a combination of three or more antiretroviral drugs, suppresses viremia below the clinical limit of detection (50 hiv-1 rna copies/ml), but latently infected resting cd4(+) t cells serve as lifelong reservoirs, and low-level viremia can be detected with special assays. recent studies have provided evidence for additional reservoirs that contribute to residual viremia but are ...200919570871
ex vivo expansion and lentiviral transduction of macaca nemestrina cd4+ t cells.macaca nemestrina is a nonhuman primate used as a model in preclinical studies of hematopoietic stem cell transplantation and adoptive transfer of t cells. adoptive t cell transfer studies typically require ex vivo expansion of substantial numbers of t cells prior to their reinfusion into the subject.200919793180
protection of stem cell-derived lymphocytes in a primate aids gene therapy model after in vivo selection.there is currently no effective aids vaccine, emphasizing the importance of developing alternative therapies. recently, a patient was successfully transplanted with allogeneic, naturally resistant ccr5-negative (ccr5delta32) cells, setting the stage for transplantation of naturally resistant, or genetically modified stem cells as a viable therapy for aids. hematopoietic stem cell (hsc) gene therapy using vectors that express various anti-hiv transgenes has also been attempted in clinical trials, ...200919888329
rt-shiv subpopulation dynamics in infected macaques during anti-hiv therapy.to study the dynamics of wild-type and drug-resistant hiv-1 rt variants, we developed a methodology that follows the fates of individual genomes over time within the viral quasispecies. single genome sequences were obtained from 3 pigtail macaques infected with a recombinant simian immunodeficiency virus containing the rt coding region from hiv-1 (rt-shiv) and treated with short-course efavirenz monotherapy 13 weeks post-infection followed by daily combination antiretroviral therapy (art) beginn ...200919889213
rt-shiv, an infectious ccr5-tropic chimeric virus suitable for evaluating hiv reverse transcriptase inhibitors in macaque models.non-nucleoside reverse transcriptase inhibitors (nnrtis) are an important category of drugs for both chemotherapy and prevention of human immunodeficiency virus type 1 (hiv-1) infection. however, current non-human primate (nhp) models utilizing simian immunodeficiency virus (siv) or commonly used chimeric shiv (siv expressing hiv-1 envelope) are inadequate due to the insensitivity to nnrtis. to develop a nhp model for evaluation of nnrti compounds, we characterized a rt-shiv virus that was assem ...200919891783
compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and il-17 production in the absence of siv infection.pigtail macaques (ptms) rapidly progress to aids after simian immunodeficiency virus (siv) infection. given the strong association between human immunodeficiency virus (hiv) and siv disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in ptms. we found that before siv infection, ptms had high levels of microbial translocation that correlated with significant damage to the structural bar ...201020357762
relative replication capacity of phenotypic siv variants during primary infections differs with route of inoculation.previous studies of human and simian immunodeficiency virus (hiv and siv) have demonstrated that adaptive mutations selected during the course of infection alter viral replicative fitness, persistence, and pathogenicity. what is unclear from those studies is the impact of transmission on the replication and pathogenicity of the founding virus population. using the siv-macaque model, we examined whether the route of infection would affect the establishment and replication of two sivmne variants o ...201020942954
genetic diversity of simian immunodeficiency virus encoding hiv-1 reverse transcriptase persists in macaques despite antiretroviral therapy.the impact of antiretroviral therapy (art) on the genetics of simian immunodeficiency virus (siv) or human immunodeficiency virus (hiv) populations has been incompletely characterized. we analyzed siv genetic variation before, during, and after art in a macaque model. six pigtail macaques were infected with an siv/hiv chimeric virus, rt-shiv(mne), in which siv reverse transcriptase (rt) was replaced by hiv-1 rt. three animals received a short course of efavirenz (efv) monotherapy before combinat ...201021084490
a comparison of lower genital tract glycogen and lactic acid levels in women and macaques: implications for hiv and siv susceptibility.understanding factors that affect heterosexual transmission of hiv in women is of great importance. lactobacilli in the lower genital tract of women utilize glycogen in vaginal epithelial cells as an energy source and produce lactic acid. the resultant vaginal acidity is believed to provide protection against hiv infection. conversely, bacterial vaginosis (bv) is characterized by less lactic acid, a higher ph, and is associated with increased susceptibility to hiv infection. because vaginal infe ...201121595610
longitudinal diffusion tensor imaging and perfusion mri investigation in a macaque model of neuro-aids: a preliminary study.the simian immunodeficiency virus (siv) infected macaque model exhibits neuropathological symptoms similar to those of hiv(+) patients, and is ideal for studying cognitive impairment and neuropathological sequelae of disease in repeated measurements. the aim of this study is to use diffusion tensor imaging (dti) and perfusion mri to longitudinally access the disease development in siv-infected monkeys under controlled conditions and to cross-validate our finding with mri studies in hiv(+) patien ...201121658455
geographic, genetic and functional diversity of antiretroviral host factor trimcyp in cynomolgus macaque (macaca fascicularis).the antiretroviral factor trim5 gene-derived isoform, trimcyp, was found in at least three species of old world monkey, rhesus (macaca mulatta), pig-tailed (macaca nemestrina), and cynomolgus macaques (macaca fascicularis). although the frequency of trimcyp has been well studied in rhesus and pig-tailed macaques, the frequency and prevalence of trimcyp in the cynomolgus macaque remain to be definitively elucidated. here, we studied the geographic and genetic diversity of trim5α/trimcyp in cynomo ...201122113010
Dynamics of Simian Immunodeficiency Virus SIVmac239 Infection in Pigtail Macaques.Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P = 0.0018) ...201222090099
characterisation of simian immunodeficiency virus-infected cells in pigtail macaques.defining which cells become infected with simian immunodeficiency virus (siv) in vivo should assist in unravelling the pathogenesis of human immunodeficiency virus (hiv)/siv infection. hiv/siv infection of cd4(+) t cells resulted in down-regulation of cd3 and cd4 surface molecules in vitro, however this phenomenon is poorly characterised in vivo. intracellular siv p27 was studied by flow cytometry in serial blood samples and lymph node samples during acute infection of 17 sivmac-infected pigtail ...201222507218
platelet activation and platelet-monocyte aggregate formation contribute to decreased platelet count during acute simian immunodeficiency virus infection in pig-tailed macaques.platelets are key participants in innate immune responses to pathogens. as a decrease in circulating platelet count is one of the initial hematologic indicators of human immunodeficiency virus (hiv) infection, we sought to determine whether decline in platelet number during acute infection results from decreased production, increased antibody-mediated destruction, or increased platelet activation in a simian immunodeficiency virus (siv)/macaque model. during acute siv infection, circulating plat ...201323852120
serial study of lymph node cell subsets using fine needle aspiration in pigtail macaques.lymphoid tissues are of intense interest for studies of the pathogenesis of human immunodeficiency virus (hiv) in humans and simian immunodeficiency virus (siv) in macaques but are relatively difficult to sample non-invasively. fine needle aspiration (fna) cytology, conventionally a diagnostic procedure for lymphadenopathy, can be used for longitudinal study of tissue cell subsets during hiv/siv infection. in this study, we serially sampled lymph node (ln) fna from pigtail macaques and studied c ...201323702165
a variant macaque-tropic human immunodeficiency virus type 1 is resistant to alpha interferon-induced restriction in pig-tailed macaque cd4+ t cells.human immunodeficiency virus type 1 (hiv-1) antagonizes innate restriction factors in order to infect and persistently replicate in a host. in a previous study, we demonstrated that hiv-1 nl4-3 with a simian immunodeficiency virus mne (sivmne) vif gene substitution (hsiv-vif-nl4-3) could infect and replicate in pig-tailed macaques (ptm), indicating that apobec3 proteins are primary barriers to transmission. because viral replication was persistent but low, we hypothesized that hsiv-vif-nl4-3 may ...201323552412
rate of aids progression is associated with gastrointestinal dysfunction in simian immunodeficiency virus-infected pigtail macaques.during hiv/siv infection, mucosal immune system dysfunction and systemic immune activation are associated with progression to aids; however, it is unclear to what extent pre-existing gastrointestinal damage relates to disease progression postinfection. pigtail macaques (ptm) are an excellent model in which to assess mucosal dysfunction in relation to hiv/siv pathogenesis, as the majority of these animals have high levels of gastrointestinal damage, immune activation, and microbial translocation ...201323401593
trivalent live attenuated influenza-simian immunodeficiency virus vaccines: efficacy and evolution of cytotoxic t lymphocyte escape in macaques.there is an urgent need for a human immunodeficiency virus (hiv) vaccine that induces robust mucosal immunity. cd8(+) cytotoxic t lymphocytes (ctls) apply substantial antiviral pressure, but ctls to individual epitopes select for immune escape variants in both hiv in humans and siv in macaques. inducing multiple simian immunodeficiency virus (siv)-specific ctls may assist in controlling viremia. we vaccinated 10 mane-a1*08401(+) female pigtail macaques with recombinant influenza viruses expressi ...201323345519
simian immunodeficiency virus infects follicular helper cd4 t cells in lymphoid tissues during pathogenic infection of pigtail macaques.t follicular helper (tfh) cells are a specialized subset of memory cd4(+) t cells that are found exclusively within the germinal centers of secondary lymphoid tissues and are important for adaptive antibody responses and b cell memory. tfh cells do not express ccr5, the primary entry coreceptor for both human immunodeficiency virus type 1 (hiv-1) and simian immunodeficiency virus (siv), and therefore, we hypothesized that these cells would avoid infection. we studied lymph nodes and spleens from ...201323325697
unraveling the pathogenesis of hiv peripheral neuropathy: insights from a simian immunodeficiency virus macaque model.peripheral neuropathy (pn) is the most frequent neurologic complication in individuals infected with human immunodeficiency virus (hiv). it affects over one third of infected patients, including those receiving effective combination antiretroviral therapy. the pathogenesis of hiv-associated peripheral neuropathy (hiv-pn) remains poorly understood. clinical studies are complicated because both hiv and antiretroviral treatment cause damage to the peripheral nervous system. to study hiv-induced per ...201424615443
comparison of the vaginal environment of macaca mulatta and macaca nemestrina throughout the menstrual cycle.pigtail macaques, macaca nemestrina (pt), are more susceptible to vaginal transmission of simian immunodeficiency virus (siv) and other sexually transmitted diseases (std) than rhesus macaques (rm). however, comparative studies to explore the reasons for these differences are lacking.201424521395
longitudinal cerebral metabolic changes in pig-tailed macaques infected with the neurovirulent virus sivsmmfgb.longitudinal cerebral metabolite changes in pig-tailed macaques inoculated with the simian immunodeficiency virus sivsmmfgb were evaluated with in vivo proton mrs at 3 t. blood sample collection, and mrs were carried out before and 2, 4, 8, 12, 16, 20, and 24 weeks after siv inoculation. significant reduction of n-acetylaspartate (naa)/creatine (cr) and choline (cho)/cr ratios in prefrontal gray matter (pgm) and glutamate/glutamine(glx)/cr ratio in striatum, and increase of myo-inositol (mi)/cr ...201425377443
linking pig-tailed macaque major histocompatibility complex class i haplotypes and cytotoxic t lymphocyte escape mutations in simian immunodeficiency virus infection.the influence of major histocompatibility complex class i (mhc-i) alleles on human immunodeficiency virus (hiv) diversity in humans has been well characterized at the population level. mhc-i alleles likely affect viral diversity in the simian immunodeficiency virus (siv)-infected pig-tailed macaque (macaca nemestrina) model, but this is poorly characterized. we studied the evolution of siv in pig-tailed macaques with a range of mhc-i haplotypes. siv(mac251) genomes were amplified from the plasma ...201425275134
a longitudinal magnetization transfer imaging evaluation of brain injury in a macaque model of neuroaids.magnetization transfer (mt) imaging has been explored in prior studies of hiv patients and showed the potential capacity to assess brain injury after hiv infection. in the present study, adult pig-tailed macaques were infected with a highly neuropathogenic virus sivsmmfgb. mt imaging was exploited to examine the monkey brains before simian immunodeficiency virus (siv) inoculation and 2, 4, 8, 12, 16, and 20 weeks post-siv inoculation. blood samples were collected from each animal for monitoring ...201525376011
elite control, gut cd4 t cell sparing, and enhanced mucosal t cell responses in macaca nemestrina infected by a simian immunodeficiency virus lacking a gp41 trafficking motif.deletion of gly-720 and tyr-721 from a highly conserved gyxxø trafficking signal in the sivmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed δgy, leads to a striking perturbation in pathogenesis in rhesus macaques (macaca mulatta). infected macaques develop immune activation and progress to aids, but with only limited and transient infection of intestinal cd4(+) t cells and an absence of microbial translocation. here we evaluated δgy in pig-tailed macaques (macaca nemestr ...201526223646
epitope-specific cd8+ t cell kinetics rather than viral variability determine the timing of immune escape in simian immunodeficiency virus infection.cd8(+) t cells are important for the control of chronic hiv infection. however, the virus rapidly acquires "escape mutations" that reduce cd8(+) t cell recognition and viral control. the timing of when immune escape occurs at a given epitope varies widely among patients and also among different epitopes within a patient. the strength of the cd8(+) t cell response, as well as mutation rates, patterns of particular amino acids undergoing escape, and growth rates of escape mutants, may affect when ...201525825438
macaque species susceptibility to simian immunodeficiency virus: increased incidence of siv central nervous system disease in pigtailed macaques versus rhesus macaques.immune pressure exerted by mhc class i-restricted cytotoxic t cells drives the development of viral escape mutations, thereby regulating hiv disease progression. nonetheless, the relationship between host immunity and hiv central nervous system (cns) disease remains poorly understood. the simian immunodeficiency virus (siv) macaque model recapitulates key features of hiv infection including development of aids and cns disease. to investigate cell-mediated immunity regulating siv cns disease prog ...201525672885
simian immunodeficiency virus infection and immune responses in the pig-tailed macaque testis.the testis is a site of immune privilege in rodents, and there is evidence that t cell responses are also suppressed in the primate testis. local immunosuppression is a potential mechanism for hiv persistence in tissue reservoirs that few studies have examined. the response of the pig-tailed macaque testis to sivmac239 infection was characterized to test this possibility. testes were surgically removed during early-chronic (10 wk) and late-chronic (24-30 wk) siv infection in 4 animals and compar ...201525605872
a depot medroxyprogesterone acetate dose that models human use and its effect on vaginal shiv acquisition risk.hormonal contraception with depot medroxyprogesterone acetate (dmpa) may increase hiv acquisition risk, but observational human studies are inconclusive, and animal models can help investigate this risk. in this study, we test the impact of a low dmpa dose, designed to resemble human contraceptive use, on simian-human immunodeficiency virus (shiv) acquisition risk in pigtail macaques (macaca nemestrina).201627355414
animal models to achieve an hiv cure.the introduction of effective antiretroviral therapy (art) has transformed hiv infection from a deadly to a chronic infection. despite its successes in reducing mortality, art fails to cure hiv allowing hiv to persist in vivo. hiv persistence under art is thought to be mediated by a combination of latent infection of long-lived cells, homeostatic proliferation of latently infected cells, anatomic sanctuaries, and low-level virus replication. to understand the contribution of specific cell types ...201627152962
inflammatory monocytes expressing tissue factor drive siv and hiv coagulopathy.in hiv infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. a better understanding of inflammatory and coagulation pathways in hiv infection is needed to optimize clinical care. markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-aids events. we identified a specific subset of monocytes that expre ...201728855397
brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir.a human immunodeficiency virus (hiv) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. despite antiretroviral therapy (art), hiv-associated neurocognitive disorders (hand) are reported in hiv-infected individuals on art. biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (csf) of hiv-infected individuals demonstrate continued effects of hiv in brain and suggest t ...201728811349
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