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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
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
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 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
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
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
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
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
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
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
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
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
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
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
in vivo fitness costs of different gag cd8 t-cell escape mutant simian-human immunodeficiency viruses for macaques.the kinetics of immune escape and reversion depend upon the efficiency of cd8 cytotoxic t lymphocytes (ctl) and the fitness cost of escape mutations. escape kinetics of three simian immunodeficiency virus gag ctl epitopes in pigtail macaques were variable; those of kp9 and af9 were faster than those of kw9. kinetics of reversion of escape mutant virus to wild type upon passage to naïve major histocompatibility complex-mismatched macaques also varied. rapid reversion occurred at kp9, gradual biph ...200717344299
human herpesvirus 6a accelerates aids progression in macaques.although hiv is the necessary and sufficient causative agent of aids, genetic and environmental factors markedly influence the pace of disease progression. clinical and experimental evidence suggests that human herpesvirus 6a (hhv-6a), a cytopathic t-lymphotropic dna virus, fosters the progression to aids in synergy with hiv-1. in this study, we investigated the effect of coinfection with hhv-6a on the progression of simian immunodeficiency virus (siv) disease in pig-tailed macaques (macaca neme ...200717360322
functional genomics analyses of differential macaque peripheral blood mononuclear cell infections by human immunodeficiency virus-1 and simian immunodeficiency virus.the pathogenicity of the primate lentiviruses, human, and simian immunodeficiency viruses, is host-specific. previous studies indicated that the highly pathogenic human lentivirus hiv-1 has markedly reduced pathogenicity compared to the pathogenic simian lentivirus siv in pigtail macaques (macaca nemestrina). we therefore hypothesized that the pigtail macaque peripheral blood mononuclear cells (mpbmcs) would respond differently to infections of hiv-1 and pathogenic siv. to elucidate the cellular ...200717507074
human immunodeficiency virus type 1 derivative with 7% simian immunodeficiency virus genetic content is able to establish infections in pig-tailed macaques.a human immunodeficiency virus type 1 (hiv-1) derivative (hiv(nl-dt5r)) containing sequences encoding a 7-amino-acid segment of ca and the entire vif gene from simian immunodeficiency virus (siv) was previously shown to establish spreading infections in cultured macaque peripheral blood mononuclear cells. to assess its replicative and disease-inducing properties in vivo, hiv(nl-dt5r) was inoculated into pig-tailed macaques. hiv(nl-dt5r) generated plasma viremia in all five of the monkeys and eli ...200717670817
novel trim5 isoforms expressed by macaca nemestrina.the trim5 family of proteins contains a ring domain, one or two b boxes, and a coiled-coil domain. the trim5alpha isoform also encodes a c-terminal b30.2(spry) domain, differences within which define the breadth and potency of trim5alpha-mediated retroviral restriction. because macaca nemestrina animals are susceptible to some human immunodeficiency virus (hiv) isolates, we sought to determine if differences exist in the trim5 gene and transcripts of these animals. we identified a two-nucleotide ...200717804491
suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy.antiretroviral therapy (art) in human immunodeficiency virus type 1 (hiv-1)-infected patients does not clear the infection and can select for drug resistance over time. not only is drug-resistant hiv-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of hiv-1, transient nonnucleoside reverse transcriptase inhibitor (nnrti) therapy given during labor can select for nnrti resis ...200717855539
killing kinetics of simian immunodeficiency virus-specific cd8+ t cells: implications for hiv vaccine strategies.both the magnitude and function of vaccine-induced hiv-specific cd8+ ctls are likely to be important in the outcome of infection. we hypothesized that rapid cytolysis by ctls may facilitate control of viral challenge. release kinetics of the cytolytic effector molecules granzyme b and perforin, as well as the expression of the degranulation marker cd107a and ifn-gamma were simultaneously studied in siv gag(164-172) kp9-specific cd8+ t cells from mane-a*10+ pigtail macaques. macaques were vaccina ...200717878354
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
characterization of an anti-lymphocyte function-associated antigen-1 antibody in a simian immunodeficiency virus-pig-tailed macaque (macaca nemestrina) model.the simian immunodeficiency virus (siv)/pig-tailed macaque (macaca nemestrina) model of acquired immune deficiency syndrome (aids) is a powerful system in which to study cell adhesion molecules and retroviral pathogenesis in vivo. preliminary experiments were conducted to examine the role of lymphocyte function-associated antigen 1 (lfa-1) in early siv infection in vivo by using an lfa-1 monoclonal antibody (mhm.23) specific to human lfa-1. in vitro studies revealed that at concentrations of > o ...200616521856
generation of hiv-1 derivatives that productively infect macaque monkey lymphoid cells.the narrow host range of human immunodeficiency virus type 1 (hiv-1) is caused in part by innate cellular factors such as apolipoprotein b mrna-editing enzyme-catalytic polypeptide-like 3g (apobec3g) and trim5alpha, which restrict virus replication in monkey cells. variant hiv-1 molecular clones containing both a 21-nucleotide simian immunodeficiency virus (siv) gag ca element, corresponding to the hiv-1 cyclophilin a-binding site, and the entire siv vif gene were constructed. long-term passage ...200617065315
early dysregulation of cripto-1 and immunomodulatory genes in the cerebral cortex in a macaque model of neuroaids.human immunodeficiency virus type 1 (hiv-1) and related primate lentiviruses are known to enter the central nervous system (cns) during the primary phase of infection. neuroinvasion by simian immunodeficiency virus and simian human immunodeficiency virus (shiv) is characterized by transient meningitis and astrocytosis. in this report, we used targeted cytokine cdna arrays to analyze cortical brain tissue from four pig-tailed macaques inoculated for 2 weeks with pathogenic shiv(50olnv) and a norm ...200617084529
mhc class i allele frequencies in pigtail macaques of diverse origin.pigtail macaques (macaca nemestrina) are an increasingly common primate model for the study of human aids. major histocompatibility complex (mhc) class i-restricted cd8(+) t cell responses are a critical part of the adaptive immune response to hiv-1 in humans and simian immunodeficiency virus (siv) in macaques; however, mhc class i alleles have not yet been comprehensively characterized in pigtail macaques. the frequencies of ten previously defined alleles (four mane-a and six mane-b) were inves ...200617096100
analysis of pigtail macaque major histocompatibility complex class i molecules presenting immunodominant simian immunodeficiency virus epitopes.successful human immunodeficiency virus (hiv) vaccines will need to induce effective t-cell immunity. we studied immunodominant simian immunodeficiency virus (siv) gag-specific t-cell responses and their restricting major histocompatibility complex (mhc) class i alleles in pigtail macaques (macaca nemestrina), an increasingly common primate model for the study of hiv infection of humans. cd8+ t-cell responses to an siv epitope, gag164-172kp9, were present in at least 15 of 36 outbred pigtail mac ...200515613296
plateau levels of viremia correlate with the degree of cd4+-t-cell loss in simian immunodeficiency virus sivagm-infected pigtailed macaques: variable pathogenicity of natural sivagm isolates.simian immunodeficiency virus from african green monkeys (sivagm) results in asymptomatic infection in its natural host species. the virus is not inherently apathogenic, since infection of pigtailed (pt) macaques (macaca nemestrina) with one isolate of sivagm results in an immunodeficiency syndrome characterized by progressive cd4+-t-cell depletion and opportunistic infections. this virus was passaged once in a pt macaque and, thus, may not be entirely reflective of the virulence of the parental ...200515795299
rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic t-lymphocyte epitope exacts a dramatic fitness cost.escape from specific t-cell responses contributes to the progression of human immunodeficiency virus type 1 (hiv-1) infection. t-cell escape viral variants are retained following hiv-1 transmission between major histocompatibility complex (mhc)-matched individuals. however, reversion to wild type can occur following transmission to mhc-mismatched hosts in the absence of cytotoxic t-lymphocyte (ctl) pressure, due to the reduced fitness of the escape mutant virus. we estimated both the strength of ...200515827187
mucosally-administered human-simian immunodeficiency virus dna and fowlpoxvirus-based recombinant vaccines reduce acute phase viral replication in macaques following vaginal challenge with ccr5-tropic shivsf162p3.further advances are required in understanding protection from aids by t cell immunity across mucosal sites of virus transmission. we analysed a set of multigenic hiv and shiv dna and fowlpoxvirus (fpv) prime and boost vaccines for immunogenicity and protective efficacy in outbred pigtail macaques when delivered via mucosal surfaces (intranasally or intrarectally). intranasally delivered dna, even when adjuvanted and given as a fine droplet spray, was neither immunogenic nor protective in macaqu ...200515985317
the pigtail macaque mhc class i allele mane-a*10 presents an immundominant siv gag epitope: identification, tetramer development and implications of immune escape and reversion.the pigtail macaque (macaca nemestrina) is a common model for the study of aids. the pigtail major histocompatibility complex class i allele mane-a*10 restricts an immunodominant simian immunodeficiency virus (siv) gag epitope (kp9) which rapidly mutates to escape t cell recognition following acute simian/human immunodeficiency virus infection. two technologies for the detection of mane-a*10 in outbred pigtail macaques were developed: reference strand-mediated conformational analysis and sequenc ...200516128923
immunodeficiency in the absence of high viral load in pig-tailed macaques infected with simian immunodeficiency virus sivsun or sivlhoest.simian immunodeficiency virus (siv) is known to result in an asymptomatic infection of its natural african monkey host. however, some siv strains are capable of inducing aids-like symptoms and death upon experimental infection of asian macaques. to further investigate the virulence of natural siv isolates from african monkeys, pig-tailed (pt) macaques were inoculated intravenously with either of two recently discovered novel lentiviruses, sivlhoest and sivsun. both viruses were apparently apatho ...200516254339
immunoglobulin-a nephropathy with crescentic glomerulonephritis in a pigtailed macaque (macaca nemestrina).a 4-year-old female pigtailed macaque (macaca nemestrina), experimentally coinfected with simian immunodeficiency virus (sivmac251) and mycobacterium bovis(bacillus calmette-guerin), was euthanatized 1 year after infection because of weight loss and labored breathing. on gross examination, both kidneys were found to be markedly enlarged (right: 54.7 g and left: 51.7 g; normal < 20 g). renal lesions were evaluated by histopathologic, immunohistochemical, and ultrastructural methods. light microsc ...200414715967
correlation of acute humoral response with brain virus burden and survival time in pig-tailed macaques infected with the neurovirulent simian immunodeficiency virus sivsmmfgb.infection of pig-tailed macaques with the simian immunodeficiency virus (siv) isolate sivsmmfgb frequently results in siv encephalitis (sive) in addition to immunodeficiency and acquired immune deficiency syndrome. we used in situ hybridization to quantitate the number of siv-infected cells in brain parenchyma, choroid plexus, and meninges from 17 macaques that developed acquired immune deficiency syndrome after infection with sivsmmfgb. siv-infected cells and histopathological lesions of sive w ...200415039205
a single amino acid change in gp41 is linked to the macrophage-only replication phenotype of a molecular clone of simian immunodeficiency virus derived from the brain of a macaque with neuropathogenic infection.simian immunodeficiency virus (siv)-related neuropathogenesis has been observed in 90% of pig-tailed macaques infected with strain sivsmmfgb, making it an excellent system for studying human immunodeficiency virus (hiv)-associated neurological disease. to investigate the genetics of siv neurovirulence, infectious molecular clones were generated from the brain of a sivsmmfgb-infected pig-tailed macaque. one clone, bpzm.12, displayed a macrophage-restricted phenotype not previously described; this ...200415246269
a real-time pcr-based method to independently sample single simian immunodeficiency virus genomes from macaques with a range of viral loads.the generation of a diverse population of viral variants is a hallmark of simian immunodeficiency virus (siv) infection. in order to address what role this diversity plays in disease progression, accurate sampling of the viral population is necessary. however, traditional pcr-based methods often rely on amplification of multiple genomes in one reaction, leading to resampling of viral genomes and potential errors in the estimations of viral diversity, especially when sequences from only one or a ...200415525323
in vitro characterization of a simian immunodeficiency virus-human immunodeficiency virus (hiv) chimera expressing hiv type 1 reverse transcriptase to study antiviral resistance in pigtail macaques.antiviral resistance is a significant obstacle in the treatment of human immunodeficiency virus type 1 (hiv-1)-infected individuals. because nonnucleoside reverse transcriptase inhibitors (nnrtis) specifically target hiv-1 reverse transcriptase (rt) and do not effectively inhibit simian immunodeficiency virus (siv) rt, the development of animal models to study the evolution of antiviral resistance has been problematic. to facilitate in vivo studies of nnrti resistance, we examined whether a siv ...200415564466
role of microglial cells in selective replication of simian immunodeficiency virus genotypes in the brain.an accelerated, consistent macaque simian immunodeficiency virus (siv) model in which over 90% of pigtailed macaques (macaca nemestrina) coinoculated with siv/17e-fr and siv/deltab670 developed encephalitis was used to determine whether central nervous system (cns) lesions are associated with the replication of specific genotypes in the brain and, more specifically, in the microglia. ten of 11 inoculated macaques had severe (n = 3), moderate (n = 5), or mild (n = 2) encephalitis at 3 months post ...200312477826
resting cd4+ t lymphocytes but not thymocytes provide a latent viral reservoir in a simian immunodeficiency virus-macaca nemestrina model of human immunodeficiency virus type 1-infected patients on highly active antiretroviral therapy.despite suppression of viremia in patients on highly active antiretroviral therapy (haart), human immunodeficiency virus type 1 persists in a latent reservoir in the resting memory cd4(+) t lymphocytes and possibly in other reservoirs. to better understand the mechanisms of viral persistence, we established a simian immunodeficiency virus (siv)-macaque model to mimic the clinical situation of patients on suppressive haart and developed assays to detect latently infected cells in the siv-macaque ...200312663799
mechanistic understanding of an altered fidelity simian immunodeficiency virus reverse transcriptase mutation, v148i, identified in a pig-tailed macaque.we have recently reported that the reverse transcriptase (rt) of sivmne 170 (170), which is a representative viral clone of the late symptomatic phase of infection with the parental strain, sivmne cl8 (cl8), has a largely increased fidelity, compared with the cl8 rt. in the present study, we analyzed the mechanistic alterations of the high fidelity 170 rt variant. first, we found that among several 170 rt mutations, only one, v148i, is solely responsible for the fidelity increase over the cl8 rt ...200312740369
characterization of a simian human immunodeficiency virus encoding the envelope gene from the ccr5-tropic hiv-1 ba-l.the tat, rev, vpu, and env genes from the monocytotropic ccr5-dependent hiv-1 ba-l isolate were substituted for homologous simian immunodeficiency virus (siv) sequences in the siv genome. the resultant shiv (shiv ba-l) replicated in ccr5-positive pm-1 cells but not in ccr5-negative cemx174 cells. infection of hos cells expressing different co-receptors showed shiv ba-l to be strictly ccr5-dependent. infection of pm-1 cells and rhesus peripheral blood mononuclear cells (pbmcs) was highly sensitiv ...200312843740
central nervous system correlates of behavioral deficits following simian immunodeficiency virus infection.despite the high incidence of cognitive and motor impairment in acquired immunodeficiency syndrome (aids) patients, the mechanisms of aids-related central nervous system (cns) pathology are not completely understood. infection with simian immunodeficiency virus (siv) in macaques provides an excellent model of aids, including human immunodeficiency virus (hiv)-induced cns pathology and cognitive/behavioral impairment. co-inoculation with two siv strains, siv/17e-fr and siv/deltab670, accelerates ...200312907390
determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies.we previously reported that high-titered neutralizing antibodies directed against the human immunodeficiency virus type 1 (hiv-1) envelope can block the establishment of a simian immunodeficiency virus (siv)/hiv chimeric virus (shiv) infection in two monkeys following passive transfer (r. shibata et al., nat. med. 5:204-210, 1999). in the present study, increasing amounts of neutralizing immunoglobulin g (igg) were administered to 15 pig-tailed macaques in order to obtain a statistically valid p ...200211836389
evolution of a human immunodeficiency virus type 1 variant with enhanced replication in pig-tailed macaque cells by dna shuffling.dna shuffling facilitated the evolution of a human immunodeficiency virus type 1 (hiv-1) variant with enhanced replication in pig-tailed macaque peripheral blood mononuclear cells (pt mpbmc). this variant consists exclusively of hiv-1-derived sequences with the exception of simian immunodeficiency virus (siv) nef. sequences spanning the gag-protease-reverse transcriptase (gag-pro-rt) region from several hiv-1 isolates were shuffled and cloned into a parental hiv-1 backbone containing siv nef. ne ...200211861859
the itam in nef influences acute pathogenesis of aids-inducing simian immunodeficiency viruses sivsm and sivagm without altering kinetics or extent of viremia.the role of the immunoreceptor tyrosine-based activation motif (itam) that is unique to the nef protein of the acutely pathogenic simian immunodeficiency virus sivsmpbj was studied in the context of two aids-inducing simian immunodeficiency virus molecular clones. nefy(+) variants of sivagm9063-2 and sivsme543-3 replicated in and induced proliferation of unstimulated pig-tailed macaque pbmc. the pathogenesis of the nefy(+) and nefy(-) clones of sivagm9063-2, sivsme543-3, and pbj6.6 were evaluate ...200211932405
innate differences between simian-human immunodeficiency virus (shiv)(ku-2)-infected rhesus and pig-tailed macaques in development of neurological disease.neurological disease associated with hiv infection results from either primary replication of the virus or a combination of virus infection and replication of opportunistic pathogens in the cns. recent studies indicate that the primary infection is mediated mainly by viruses that utilize ccr5 as the coreceptor; it is not known whether the syndrome can be mediated by viruses that use the cxcr4 coreceptor. the macaque model of the disease using simian immunodeficiency virus (siv) has confirmed tha ...200212033765
pathogenic and nef-interrupted simian-human immunodeficiency viruses traffic to the macaque cns and cause astrocytosis early after inoculation.several studies have shown that deletion of the nef gene of simian immunodeficiency virus (siv) and simian-human immunodeficiency virus (shiv) results in attenuated viruses. however, studies have not critically examined trafficking of attenuated viruses to the central nervous system (cns) at early stages after inoculation. in this study, we investigated the colocalization of pathogenic and vpu-negative, nef-interrupted shivs at early stages following inoculation. the first virus, designated shiv ...200212036316
engineered cd4- and cxcr4-using simian immunodeficiency virus from african green monkeys is neutralization sensitive and replicates in nonstimulated lymphocytes.during human immunodeficiency virus type 1 (hiv-1) infection, disease progression correlates with the occurrence of variants using the coreceptor cxcr4 for cell entry. in contrast, apathogenic simian immunodeficiency virus (siv) from african green monkeys (sivagm), specifically the molecular virus clone sivagm3mc, uses ccr5, bob, and bonzo as coreceptors throughout the course of infection. the influence of an altered coreceptor usage on sivagm3mc replication was studied in vitro and in vivo. the ...200212368305
capture and transfer of simian immunodeficiency virus by macaque dendritic cells is enhanced by dc-sign.dendritic cells (dcs) are among the first cells encountered by human and simian immunodeficiency virus (hiv and siv) following mucosal infection. because these cells efficiently capture and transmit virus to t cells, they may play a major role in mediating hiv and siv infection. recently, a c-type lectin protein present on dcs, dc-specific icam-3-grabbing nonintegrin (dc-sign), was shown to efficiently bind and present hiv and siv to cd4(+), coreceptor-positive cells in trans. however, the signi ...200212414925
functional analyses of natural killer cells in macaques infected with neurovirulent simian immunodeficiency virus.clearance of hiv and siv from the peripheral blood by the cellular immune system lessens the viral burden in infected individuals and may have an impact on virus infection of the cns and the development of cns lesions. however, the role of immune responses in preventing or limiting cns infection has not been clearly defined. we investigated the role of natural killer cells in the outcome of siv infection of macaques as a model for humans with aids and hiv encephalitis. in our study, six pig-tail ...200111519478
cd4-independent, ccr5-dependent simian immunodeficiency virus infection and chemotaxis of human cells.most simian immunodeficiency virus (siv), human immunodeficiency virus type 2 (hiv-2), and hiv-1 infection of host peripheral blood mononuclear cells (pbmcs) is cd4 dependent. in some cases, x4 hiv-1 chemotaxis is cd4 independent, and cross-species transmission might be facilitated by cd4-independent entry, which has been demonstrated for some siv strains in cd4(-) non-t cells. as expected for ccr5-dependent virus, siv required cd4 on rhesus and pigtail macaque pbmcs for infection and chemotaxis ...200010888609
simian-human immunodeficiency virus-associated nephropathy in macaques.a number of chimeric simian-human immunodeficiency virus (shiv) viruses containing tat, rev, vpu, and env from hiv-1 (strain hxbc2) in a genetic background of simian immunodeficiency virus (siv(mac)239) have been derived from the parental nonpathogenic shiv-4 virus. in this article we examine the renal pathology associated with the derivation of these pathogenic shiv strains. the first of the pathogenic shivs, shiv(ku-1), is associated with rapid cd4(+) t cell loss and opportunistic infections a ...200010957726
mucosal challenge of macaca nemestrina with simian immunodeficiency virus (siv) following siv nucleocapsid mutant dna vaccination.a simian immunodeficiency virus (siv)(mne) dna clone was constructed that produces viruses containing a four amino acid deletion in the second zinc finger of the nucleocapsid (nc) domain of the gag polyprotein. viruses produced from this clone, although non-infectious both in vitro and in vivo, complete a majority of the steps in a single retroviral infection cycle. eight pig-tailed macaques (macaca nemestrina) were inoculated intramuscularly and subcutaneously three times over the course of 24 ...200011085583
protection of macaca nemestrina from disease following pathogenic simian immunodeficiency virus (siv) challenge: utilization of siv nucleocapsid mutant dna vaccines with and without an siv protein boost.molecular clones were constructed that express nucleocapsid (nc) deletion mutant simian immunodeficiency viruses (sivs) that are replication defective but capable of completing virtually all of the steps of a single viral infection cycle. these steps include production of particles that are viral rna deficient yet contain a full complement of processed viral proteins. the mutant particles are ultrastructurally indistinguishable from wild-type virus. similar to a live attenuated vaccine, this app ...200011090194
nucleocapsid protein zinc-finger mutants of simian immunodeficiency virus strain mne produce virions that are replication defective in vitro and in vivo.all retroviruses (except the spumaretroviruses) contain a nucleocapsid (nc) protein that encodes one or two copies of the zn2+-finger sequence -cys-x2-cys-x4-his-x4-cys-. this region has been shown to be essential for recognition and packaging of the genomic rna during virion particle assembly. additionally, this region has been shown to be involved in early infection events in a wide spectrum of retroviruses, including mammalian type c [e.g., murine leukemia virus (mulv)], human immunodeficienc ...19999918884
coinfection of macaques with simian immunodeficiency virus and simian t cell leukemia virus type i: effects on virus burdens and disease progression.to test the hypothesis that coinfection with human immunodeficiency virus (hiv) and human t cell leukemia/lymphoma virus types i or ii (htlv-i or -ii) accelerates progression to aids, pig-tailed macaques were inoculated with the simian counterparts, siv and stlv-i. during 2 years of follow-up of singly and dually infected macaques, no differences in siv burdens, onset of disease, or survival were detected. however, in the first coinfected macaque that died of aids (1 year after infection), >50% ...19999952366
virus threshold determines disease in sivsmmpbj14-infected macaques.simian immunodeficiency virus (siv) variant sivsmmpbj14 is unique in producing an acutely lethal enteropathic syndrome in pigtail macaques. to determine whether the nature of the pbj14 disease would be attenuated by decreasing virus input and to relate tissue virus burden to the severity of disease, we infected pigtail macaques with serial 10-fold doses of sivsmmpbj14 clone bcl.3 spanning 10(-2) through 10(4)tcid50. the results revealed a strikingly narrow difference between minimum infectious a ...199910029250
in vivo cell and tissue tropism of sivsmmpbj14-bcl.3.to gain insight into the unique pathogenicity of simian immunodeficiency virus (siv) variant pbj14, which produces an acutely lethal enteropathic syndrome in infected pigtail macaques, we investigated the cell and tissue tropisms of a highly pathogenic biologic clone (bcl.3) of sivsmmpbj14. to compare the relative amount of viral antigen in lymphoid organs of infected macaques we used an objective semiquantitative immunohistochemistry (sqihc) assay. we found that in all animals viral antigen loa ...199910029252
pathogenicity and comparative evolution in vivo of the transitional quasispecies sivsmmpbj8.during 14 months of infection of a pig-tailed macaque, the acutely lethal simian immunodeficiency virus sivsmmpbj14 (siv-pbj14) evolved from the minimally pathogenic strain sivsmm9. the virus isolated at 8 months (siv-pbj8) exhibited properties of both sivsmm9 and siv-pbj14, indicating that a phenotypic transition occurred between 6 and 10 months. to assess the influence that this new composition of biologic properties might have on pathogenicity, three pig-tailed macaques were inoculated intrav ...199910364501
postinoculation pmpa treatment, but not preinoculation immunomodulatory therapy, protects against development of acute disease induced by the unique simian immunodeficiency virus sivsmmpbj.the fatal disease induced by sivsmmpbj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. while the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. these biological characteristics include induction of peripheral blood mononuclear cell (pbmc) proliferation, upregulation of activation markers and fas ligand expression, and increased levels of apopto ...199910482616
experimental infection of rhesus and pig-tailed macaques with macaque rhadinoviruses.the recognition of naturally occurring rhadinoviruses in macaque monkeys has spurred interest in their use as models for human infection with kaposi sarcoma-associated herpesvirus (human herpesvirus 8). rhesus macaques (macaca mulatta) and pig-tailed macaques (macaca nemestrina) were inoculated intravenously with rhadinovirus isolates derived from these species (rhesus rhadinovirus [rrv] and pig-tailed rhadinovirus [prv]). nine rhadinovirus antibody-negative and two rhadinovirus antibody-positiv ...199910559350
high viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis.aids dementia and encephalitis are complications of aids occurring most frequently in patients who are immunosuppressed. the simian immunodeficiency virus (siv) model used in this study was designed to reproducibly induce aids in macaques in order to examine the effects of a neurovirulent virus in this context. pigtailed macaques (macaca nemestrina) were coinoculated with an immunosuppressive virus (siv/deltab670) and a neurovirulent molecularly cloned virus (siv/17e-fr), and more than 90% of th ...199910559366
the disruption of macaque cd4+ t-cell repertoires during the early simian immunodeficiency virus infection.t-cell receptor (tcr) complementarily determining region 3 (cdr3) spetratyping analysis was employed to assess the ability of an aids virus to disrupt cd4 + t-cell repertoires during the primary infection. rhesus and pig-tailed macaques infected with simian immunodeficiency virus (siv)mac 251 and sivsmmfgb, respectively, were evaluated. following siv infection, the macaques exhibited an apparent decline of cd4 + peripheral blood lymphocyte (pbl) counts, which was associated with a change in cdr3 ...199910593483
use of herpesvirus saimiri-immortalized macaque cd4(+) t cell clones as stimulators and targets for assessment of ctl responses in macaque/aids models.herpesvirus saimiri (hvs), a nonhuman primate gamma herpes virus, was used to immortalize pig-tailed macaque cd4(+) t lymphocytes. the hvs-immortalized t cell lines were used to develop cd4(+) t cell clones from two animals. three cd4(+) t cell clones were further characterized for the expression of cell surface markers. all expressed cd2, cd4, cd58, cd69 and cd80 and therefore resembled activated t cells. these clones required exogenous il-2 for efficient growth and were found to be highly susc ...199910594353
a lymph node-derived cytopathic simian immunodeficiency virus mne variant replicates in nonstimulated peripheral blood mononuclear cells.lymph nodes (lns) are sites of active human immunodeficiency virus type 1 (hiv-1) and simian immunodeficiency virus (siv) replication and disease at both early and late stages of infection. consequently, variant viruses that replicate efficiently and subsequently cause immune dysfunction may be harbored in this tissue. to determine whether ln-associated sivs have an increased capacity to replicate and induce cytopathology, a molecular clone of siv was isolated directly from dna extracted from un ...19989420221
the u3 promoter and the nef gene of simian immunodeficiency virus (siv) smmpbj1.9 do not confer acute pathogenicity upon sivagm.two chimeric proviruses comprising the u3 promoter and the nef gene of simian immunodeficiency virus (siv) smmpbj1.9 in addition to other genomic regions of sivagm3mc from african green monkeys (cercopithecus aethiops) were constructed. the derived chimeric viruses (sivagm3mc/sivsmmpbj1.9) were both able to replicate in nonstimulated peripheral blood leukocytes from pig-tailed macaques (macaca nemestrina), a biological property often correlated with acute pathogenicity. however, only one of the ...19989525679
simian-human immunodeficiency virus (shiv) containing the nef/long terminal repeat region of the highly virulent sivsmmpbj14 causes pbj-like activation of cultured resting peripheral blood mononuclear cells, but the chimera showed no increase in virulence.sivsmmpbj14 is a highly pathogenic lentivirus which causes acute diarrhea, rash, massive lymphocyte proliferation predominantly in the gastrointestinal tract, and death within 7 to 14 days. in cell culture, the virus has mitogenic effects on resting macaque t lymphocytes. in contrast, sivmac239 causes aids in rhesus macaques, generally within 2 years after inoculation. in a previous study, replacement of amino acid residues 17 and 18 of the nef protein of sivmac239 with the corresponding amino a ...19989573293
the tyrosine-17 residue of nef in sivsmmpbj14 is required for acute pathogenesis and contributes to replication in macrophages.the variant simian immunodeficiency virus termed sivsmmpbj14 induces a rapidly fatal disease in pig-tailed macaques. the acute pathogenic effects of this virus appear to be associated with at least two in vitro characteristics: the ability to induce lymphocyte proliferation; and the ability to replicate in unstimulated pbmc. two of the amino acids in nef of pbj14 (the no. 17 residue, tyrosine, and the no. 18 residue, glutamic acid) appear to be linked to the virus' ability to induce lymphocyte a ...19989601497
viral genetic evolution in macaques infected with molecularly cloned simian immunodeficiency virus correlates with the extent of persistent viremia.genetic evolution of the simian immunodeficiency virus (siv) envelope glycoprotein was evaluated in a group of six macaques (macaca nemestrina) infected with the molecularly cloned, moderately pathogenic sivsm62d. the extent of envelope evolution was subsequently evaluated within the context of the individual pattern of viremia and disease outcome. two macaques in this cohort developed aids by 1.5 years postinoculation (progressors), whereas the remaining four macaques remained asymptomatic (non ...19989658091
down-modulation of the zap-70 protein tyrosine kinase in macaque t lymphocytes infected with sivsmmpbj14.the simian immunodeficiency virus siv-pbj14 is the most virulent primate lentivirus identified to date. other siv strains, including the parental sivsmm9, require mitogen-activated peripheral blood mononuclear cells (pbmc) for replication in vitro; however, siv-pbj14 replicates in quiescent pig-tailed macaque pbmc and induces cellular proliferation, consistent with its in vivo pathogenesis. to identify mechanisms involved in siv-pbj14-induced t-cell proliferation, kinases important in early t-ce ...19989747955
isolation and characterization of a neuropathogenic simian immunodeficiency virus derived from a sooty mangabey.transfusion of blood from a simian immunodeficiency virus (siv)- and simian t-cell lymphotropic virus-infected sooty mangabey (designated fgb) to rhesus and pig-tailed macaques resulted in the development of neurologic disease in addition to aids. to investigate the role of siv in neurologic disease, virus was isolated from a lymph node of a pig-tailed macaque (designated pgm) and the cerebrospinal fluid of a rhesus macaque (designated ron2) and passaged to additional macaques. siv-related neuro ...19989765429
a molecularly cloned, pathogenic, neutralization-resistant simian immunodeficiency virus, sivsme543-3.an infectious molecular clone of simian immunodeficiency virus sivsm was derived from a biological isolate obtained late in disease from an immunodeficient rhesus macaque (e543) with siv-induced encephalitis. the molecularly cloned virus, sivsme543-3, replicated well in macaque peripheral blood mononuclear cells and monocyte-derived macrophages and resisted neutralization by heterologous sera which broadly neutralized genetically diverse siv variants in vitro. sivsme543-3 was infectious and indu ...19978995688
animal model of mucosally transmitted human immunodeficiency virus type 1 disease: intravaginal and oral deposition of simian/human immunodeficiency virus in macaques results in systemic infection, elimination of cd4+ t cells, and aids.chimeric simian/human immunodeficiency virus (shiv) consists of the env, vpu, tat, and rev genes of human immunodeficiency virus type 1 (hiv-1) on a background of simian immunodeficiency virus (siv). we derived a shiv that caused cd4+ cell loss and aids in pig-tailed macaques (s. v. joag, z. li, l. foresman, e. b. stephens, l. j. zhao, i. adany, d. m. pinson, h. m. mcclure, and o. narayan, j. virol. 70:3189-3197, 1996) and used a cell-free stock of this virus (shiv(ku-1)) to inoculate macaques b ...19979094679
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