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simian immunodeficiency virus sivmac239deltanef vaccination elicits different tat28-35sl8-specific cd8+ t-cell clonotypes compared to a dna prime/adenovirus type 5 boost regimen in rhesus macaques.different human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) vaccine vectors expressing the same viral antigens can elicit disparate t-cell responses. within this spectrum, replicating variable vaccines, like sivmac239?nef, appear to generate particularly efficacious cd8(+) t-cell responses. here, we sequenced t-cell receptor ß-chain (trb) gene rearrangements from immunodominant mamu-a 01-restricted tat(28-35)sl8-specific cd8(+) t-cell populations together with the correspond ...201121270159
functional analysis of frequently expressed chinese rhesus macaque mhc class i molecules mamu-a1*02601 and mamu-b*08301 reveals hla-a2 and hla-a3 supertypic specificities.the simian immunodeficiency virus (siv)-infected indian rhesus macaque (macaca mulatta) is the most established model of hiv infection and aids-related research, despite the potential that macaques of chinese origin is a more relevant model. ongoing efforts to further characterize the chinese rhesus macaques' major histocompatibility complex (mhc) for composition and function should facilitate greater utilization of the species. previous studies have demonstrated that chinese-origin m. mulatta ( ...201121274527
double-positive cd21+cd27+ b cells are highly proliferating memory cells and their distribution differs in mucosal and peripheral tissues.several b-cell defects arise in hiv infected patients, particularly in patients with chronic infection and high viral load. loss of memory b cells (cd27(+) b cells) in peripheral blood and lymphoid tissues is one of the major b cell dysfunctions in hiv and simian immunodeficiency virus (siv) infection. despite several studies, definitive identification of memory b cells based on cd27 surface expression has not been described. similarly, the rates of cell turnover in different b cell subpopulatio ...201121304587
epitope-specific cd8+ t lymphocytes cross-recognize mutant simian immunodeficiency virus (siv) sequences but fail to contain very early evolution and eventual fixation of epitope escape mutations during siv infection.human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) evade containment by cd8(+) t lymphocytes through focused epitope mutations. however, because of limitations in the numbers of viral sequences that can be sampled, traditional sequencing technologies have not provided a true representation of the plasticity of these viruses or the intensity of cd8(+) t lymphocyte-mediated selection pressure. moreover, the strategy by which cd8(+) t lymphocytes contain evolving viral quasi ...201121307185
cryptosporidiosis in rhesus macaques challenged during acute and chronic phases of siv infection.abstract the intestinal immune dysfunction due to loss of mucosal and peripheral cd4(+) t cells in individuals with hiv/aids is presumably responsible for the establishment of persistent cryptosporidiosis. simian immunodeficiency virus (siv)-infected macaques were used to investigate the phase/timing in siv infection, which permits a self-limiting cryptosporidium parvum infection to become persistent in immunodeficient hosts because of significant mucosal immune defects. two groups of siv-infect ...201121314434
long-term control of simian immunodeficiency virus mac251 viremia to undetectable levels in half of infected female rhesus macaques nasally vaccinated with simian immunodeficiency virus dna/recombinant modified vaccinia virus ankara.the efficacy of two siv dna plus recombinant modified vaccinia virus ankara nasal vaccine regimens, one combined with plasmids expressing il-2 and il-15, the other with plasmids expressing gm-csf, il-12, and tnf-a, which may better stimulate humoral responses, was evaluated in two female rhesus macaque groups. vaccination stimulated significant siv-specific mucosal and systemic cell-mediated immunity in both groups, whereas siv-specific iga titers were sporadic and igg titers negative. all vacci ...201121317390
characterization and allelic polymorphisms of rhesus macaque (macaca mulatta) igg fc receptor genes.macaque models are invaluable for aids research. indeed, initial development of hiv-1 vaccines relies heavily on simian immunodeficiency virus-infected rhesus macaques. neutralizing antibodies, a major component of anti-hiv protective responses, ultimately interact with fc receptors on phagocytic and natural killer cells to eliminate the pathogen. despite the major role that fc receptors play in protective responses, there is very limited information available on these molecules in rhesus macaqu ...201121327607
topical nonnucleoside reverse transcriptase inhibitor mc 1220 partially prevents vaginal rt-shiv infection of macaques.abstract the availability of an effective vaginal microbicide would be a major step toward containment of hiv transmission as well as allowing women self-protection against hiv infection. here we evaluated the efficacy of vaginal application of the potent nonnucleoside reverse transcriptase inhibitor (nnrti) mc 1220 against vaginal challenge of macaques with rt-shiv, a chimeric simian immunodeficiency virus (siv) containing the reverse transcriptase (rt) gene of hiv-1. challenge infection of mon ...201121332419
Interleukin-21 administration to rhesus macaques chronically infected with simian immunodeficiency virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replication.We have previously shown that interleukin-21, a pleiotropic C ?-chain signaling cytokine, induces the expression of the cytotoxic molecules granzyme B (GrB) and perforin in vitro in CD8 T cells and NK cells of chronically HIV infected individuals. In this pilot study, four chronically SIV infected rhesus macaques (RM) in late-stage disease were given two doses of recombinant MamuIL-21, 50 µg/kg, intravenously 7 days apart, followed by one subcutaneous dose, 100 µg/kg, 23 days after the second do ...201121996099
SIVmac239 MVA vaccine with and without a DNA prime, similar prevention of infection by a repeated dose SIVsmE660 challenge despite different immune responses.BACKGROUND: Vaccine regimens using different agents for priming and boosting have become popular for enhancing T cell and Ab responses elicited by candidate HIV/AIDS vaccines. Here we use a simian model to evaluate immunogenicity and protective efficacy of a recombinant modified vaccinia Ankara (MVA) vaccine in the presence and absence of a recombinant DNA prime. The simian vaccines and regimens represent prototypes for candidate HIV vaccines currently undergoing clinical testing. METHOD: Recomb ...201122178526
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
vaccine protection against simian immunodeficiency virus in monkeys using recombinant gamma-2 herpesvirus.recombinant strains of replication-competent rhesus monkey rhadinovirus (rrv) were constructed in which strong promoter/enhancer elements were used to drive expression of simian immunodeficiency virus (siv) env or gag or a rev-tat-nef fusion protein. cultured rhesus monkey fibroblasts infected with each recombinant strain were shown to express the expected protein. three rrv-negative and two rrv-positive rhesus monkeys were inoculated intravenously with a mixture of these three recombinant rrvs. ...201121900170
early short-term antiretroviral therapy is associated with a reduced prevalence of cd8(+)foxp3(+) t cells in simian immunodeficiency virus-infected controller rhesus macaques.regulatory t cells contain a mix of cd4 and cd8 t cell subsets that can suppress immune activation and at the same time suppress immune responses, thereby contributing to disease progression. recent studies have shown that an increased prevalence of cd8(+)foxp3(+) t regulatory cells was associated with immune suppression and diminished viral control in simian immunodeficiency virus (siv)-infected rhesus macaques. preventing an increase in the prevalence of cd8 t regulatory subsets is likely to l ...201121142402
genital tract sequestration of siv following acute infection.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 m ...201121379569
ulcerative cheilitis in a rhesus macaque.a 2-year-old, female, simian immunodeficiency virus e543-infected rhesus macaque (macaca mulatta) was presented for necropsy following euthanasia due to a history of diarrhea, weight loss, and a small, round ulcer along the left labial commissure. histopathologic examination of the ulcer revealed infiltration by large numbers of degenerate and nondegenerate neutrophils and macrophages admixed with syncytial epithelial cells. rare epithelial cells contained herpetic inclusion bodies. these cells ...201121383117
specific pathogen-free status alters immunophenotype in rhesus macaques: implications for the study of simian immunodeficiency virus.abstract the repertoire of viruses to which research primates are exposed, even in the absence of clinical disease, may contribute to experimental confounding. in this study we examined whether standard specific pathogen-free (spf) rhesus macaques exposed to a wider spectrum of enzootic viruses and expanded spf macaques derived to exclude a greater number of viral agents would display alterations in immune activation or immune cell populations. given the impact of immunophenotype on human immuno ...201121391843
the nonnucleoside reverse transcriptase inhibitor miv-150 in carrageenan gel prevents rectal transmission of simian/human immunodeficiency virus infection in macaques.development of a microbicide that prevents rectal transmission of human immunodeficiency virus (hiv) is a vital component in reducing hiv spread. we recently demonstrated that a formulation of the nonnucleoside reverse transcriptase inhibitor (nnrti) miv-150 in carrageenan reduced vaginal infection of macaques with simian immunodeficiency virus sivmac239 with hiv-1(hxb2) reverse transcriptase (shiv-rt). herein, we performed the first testing of miv-150-carrageenan against rectal infection. rhesu ...201121411526
morphine potentiates neuropathogenesis of siv infection in rhesus macaques.despite the advent of antiretroviral therapy, complications of hiv-1 infection with concurrent drug abuse are an emerging problem. opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. their effect on the pathogenesis of hiv-1 infection however remains controversial. using the simian immunodeficiency virus/macaque model of hiv pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. sixteen r ...201121431470
early induction of polyfunctional simian immunodeficiency virus (siv)-specific t lymphocytes and rapid disappearance of siv from lymph nodes of sooty mangabeys during primary infection.although the cellular immune response is essential for controlling siv replication in asian macaques, its role in maintaining nonpathogenic siv infection in natural hosts such as sooty mangabeys (sm) remains to be defined. we have previously shown that similar to rhesus macaques (rm), sm are able to mount a t lymphocyte response against siv infection. to investigate early control of siv replication in natural hosts, we performed a detailed characterization of siv-specific cellular immunity and v ...201121441446
antibody-dependent cell-mediated viral inhibition emerges after simian immunodeficiency virus sivmac251 infection of rhesus monkeys coincident with gp140-binding antibodies and is effective against neutralization-resistant viruses.antibody-dependent cell-mediated viral inhibition (adcvi) is an attractive target for vaccination because it takes advantage of both the anamnestic properties of an adaptive immune response and the rapid early response characteristics of an innate immune response. effective utilization of adcvi in vaccine strategies will depend on an understanding of the natural history of adcvi during acute and chronic human immunodeficiency virus type 1 (hiv-1) infection. we used the simian immunodeficiency vi ...201121450829
tolerance to chronic delta-9-tetrahydrocannabinol (δ⁹-thc) in rhesus macaques infected with simian immunodeficiency virus.although δ⁹-thc has been approved to treat anorexia and weight loss associated with aids, it may also reduce well-being by disrupting complex behavioral processes or enhancing hiv replication. to investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or δ⁹-thc before and after inoculation with simian immunodeficiency virus (siv(mac251), 100 tcid₅₀/ml, i.v.). prior to chronic δ⁹- ...201121463073
cd8(+) lymphocyte depletion without siv infection does not produce metabolic changes or pathological abnormalities in the rhesus macaque brain.background simian immunodeficiency virus (siv) infection and persistent cd8(+) lymphocyte depletion rapidly leads to encephalitis and neuronal injury. the objective of this study is to confirm that cd8 depletion alone does not induce brain lesions in the absence of siv infection. methods four rhesus macaques were monitored by proton magnetic resonance spectroscopy ((1) h-mrs) before and biweekly after anti-cd8 antibody treatment for 8 weeks and compared with four siv-infected animals. post-mor ...201121463330
chronic δ-9-tetrahydrocannabinol administration increases lymphocyte cxcr4 expression in rhesus macaques.cannabinoids have been reported to produce various immunomodulatory effects, which could potentially impact the host response to bacterial or viral infection. we have recently demonstrated that chronic δ-9-tetrahydrocannabinol (thc; 0.32 mg/kg i.m., bid) decreased early mortality in rhesus macaques infected with simian immunodeficiency virus (siv). however, the possibility that prolonged thc administration affects lymphocyte counts, phenotype, and proliferation indices has not been addressed. we ...201121484257
immunization with recombinant hla class i and ii, hiv-1 gp140 and siv p27 elicits protection against heterologous shiv infection in rhesus macaques.mhc molecules expressed on the surface of hiv are potential targets for neutralising antibodies. since mhc molecules are polymorphic non-self mhc can also be immunogenic. we have used combinations of novel recombinant hla class i and ii and hiv/siv antigens, all linked to dextran, to investigate if they can elicit protective immunity against heterologous shiv challenge in rhesus macaques. three groups of animals were immunized with hla (group 1, n=8), trimeric yu2 hiv-1 gp140 and siv p27 (hiv/si ...201121490092
significant protection against high-dose simian immunodeficiency virus challenge conferred by a new prime-boost vaccine regimen.we constructed vaccine vectors based on live recombinant vesicular stomatitis virus (vsv) and a semliki forest virus (sfv) replicon (sfvg) that propagates through expression of the vsv glycoprotein (g). these vectors expressing simian immunodeficiency virus (siv) gag and env proteins were used to vaccinate rhesus macaques with a new heterologous prime-boost regimen designed to optimize induction of antibody. six vaccinated animals and six controls were then given a high-dose mucosal challenge wi ...201121490100
significant genetic heterogeneity of the sivmac251 viral swarm derived from different sources.infecting rhesus macaques (macaca mulatta) with the simian immunodeficiency virus (siv) is an established animal model of human immunodeficiency virus (hiv) pathogenesis. many studies have used various derivatives of the sivmac251 viral swarm to investigate several aspects of the disease, including transmission, progression, response to vaccination and siv/hiv associated neurological disorders. however, the lack of standardization of the infecting inoculum complicates comparative analyses. we in ...201121524235
dominant induction of vaccine antigen-specific cytotoxic t lymphocyte responses after simian immunodeficiency virus challenge.cytotoxic t lymphocyte (ctl) responses are crucial for the control of human and simian immunodeficiency virus (hiv and siv) replication. a promising aids vaccine strategy is to induce ctl memory resulting in more effective ctl responses post-viral exposure compared to those in natural hiv infections. we previously developed a ctl-inducing vaccine and showed siv control in some vaccinated rhesus macaques. these vaccine-based siv controllers elicited vaccine antigen-specific ctl responses dominant ...201121531211
extended safety and efficacy studies of a live attenuated double leucine and pantothenate auxotroph of mycobacterium tuberculosis as a vaccine candidate.we have previously described the development of a live, fully attenuated mycobacterium tuberculosis (mtb) vaccine candidate strain with two independent attenuating auxotrophic mutations in leucine and pantothenate biosynthesis. in the present work, those studies have been extended to include testing for protective efficacy in a long-term guinea pig survival model and safety testing in the highly tuberculosis susceptible rhesus macaque. to model the safety of the δleud δpancd strain in hiv-infect ...201121549795
diverse peptide presentation of rhesus macaque mhc class i mamu-a*02 revealed by two peptide-complex structures and insights into siv immune escape.mhc class i (mhc i)-restricted cd8(+) t-cell responses play a pivotal role in anti-hiv immunity and the control of viremia. rhesus macaque is an important animal model for hiv-related research. among the mhc i alleles of rhesus macaque, mamu-a*02 is prevalent, presenting in ≥ 20% of macaques. in this study, we determined the crystal structure of mamu-a*02, the second structure-determined mhc i from rhesus macaque after mamu-a*01. the peptide presentation characteristics of mamu-a*02 are exhibite ...201121561910
profound early control of highly pathogenic siv by an effector memory t-cell vaccine.the acquired immunodeficiency syndrome (aids)-causing lentiviruses human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) effectively evade host immunity and, once established, infections with these viruses are only rarely controlled by immunological mechanisms. however, the initial establishment of infection in the first few days after mucosal exposure, before viral dissemination and massive replication, may be more vulnerable to immune control. here we report that siv vacci ...201121562493
antibody-dependent cell-mediated cytotoxicity in simian immunodeficiency virus-infected rhesus monkeys.with the recent demonstration in the rv144 thai trial that a vaccine regimen that does not elicit neutralizing antibodies or cytotoxic t lymphocytes may confer protection against hiv-1 infection, attention has turned to non-neutralizing antibodies as a possible mechanism of vaccine protection. in the current study, we evaluated the kinetics of the antibody-dependent cell mediated cytotoxicity (adcc) response during acute and chronic sivmac251 infection of rhesus monkeys. we first adapted a flow- ...201121593181
simian immunodeficiency virus infection in rhesus macaques induces selective tissue specific b cell defects in double positive cd21+cd27+ memory b cells.b cell dysfunction represents a central feature in hiv infection and pathogenesis. our recent studies have shown that peripheral and lymphoid double positive cd21+cd27+ b cells were able to become activated and proliferate at higher rates than other b cell subpopulations. increased proliferation of tonsillar memory b cells was identified compared to other tissues examined. here, we demonstrate the decreased proliferation of tonsillar memory (cd21+cd27+) b cells during acute siv infection also su ...201121622026
cutting edge: t cells monitor n-myristoylation of the nef protein in simian immunodeficiency virus-infected monkeys.the use of the host cellular machinery is essential for pathogenic viruses to replicate in host cells. hiv and siv borrow the host-derived n-myristoyl-transferase and its substrate, myristoyl-coa, for coupling a saturated c(14) fatty acid (myristic acid) to the n-terminal glycine residue of the nef protein. this biochemical reaction, referred to as n-myristoylation, assists its targeting to the plasma membrane, thereby supporting the immunosuppressive activity proposed for the nef protein. in th ...201121653836
vaccination against heterologous r5 clade c shiv: prevention of infection and correlates of protection.a safe, efficacious vaccine is required to stop the aids pandemic. disappointing results from the step trial implied a need to include humoral anti-hiv-1 responses, a notion supported by rv144 trial data even though correlates of protection are unknown. we vaccinated rhesus macaques with recombinant simian immunodeficiency virus (siv) gag-pol particles, hiv-1 tat and trimeric clade c (hiv-c) gp160, which induced cross-neutralizing antibodies (nabs) and robust cellular immune responses. after fiv ...201121799765
growth-associated protein-43 and ephrin b3 induction in the brain of adult siv-infected rhesus macaques.understanding the mechanisms of neuronal regeneration and repair in the adult central nervous system is a vital area of research. using a rhesus lentiviral encephalitis model, we sought to determine whether recovery of neuronal metabolism after injury coincides with the induction of two important markers of synaptodendritic repair: growth-associated protein-43 (gap-43) and ephrin b3. we examined whether the improvement of neuronal metabolism with combined anti-retroviral therapy (cart) after sim ...201121789725
reactivation of latent tuberculosis in rhesus macaques by coinfection with simian immunodeficiency virus.background  tuberculosis (tb) and aids together present a devastating public health challenge. over 3 million deaths every year are attributed to these twin epidemics. annually, ∼11 million people are coinfected with hiv and mycobacterium tuberculosis (mtb). aids is thought to alter the spontaneous rate of latent tb reactivation. methodology  macaques are excellent models of both tb and aids. therefore, it is conceivable that they can also be used to model coinfection. using clinical, pathologic ...201121781131
trim5 modulates penile mucosal acquisition of simian immunodeficiency virus in rhesus monkeys.there is considerable variability in host susceptibility to hiv-1 infections, but the host genetic determinants of that variability are not well-understood. in addition to serving as a block for cross-species retroviral infection, trim5 has recently been shown to play a central role in limiting primate immunodeficiency virus replication. we hypothesized that trim5 may also contribute to susceptibility to mucosal acquisition of siv in rhesus monkeys. we explored this hypothesis by establishing 3 ...201121775457
elevated frequency of cd1c+ myeloid dendritic cells in the peripheral blood mononuclear cells of simian/human immunodeficiency virus (shiv) and simian immunodeficiency virus (siv) repeatedly infected chinese rhesus macaques.cd1c+ myeloid dendritic cells (mdcs) in the peripheral blood of 30 shiv-sf162p4 and sivmac251 sequentially infected chinese rhesus macaques were examined by flow cytometry to obtain further insight into mdc alterations in hiv/aids. the cd1c+ cells were found to be mononuclear leukocytes rather than granulocytes, and most of them expressed cd20. cd1c+mdcs (cd1c+cd20-) consisted of two morphological subsets: the granular and the large cd1c+mdcs. the expression of hla-dr, cd86, and cd11b, but no cc ...201121714961
low levels of siv infection in sooty mangabey central memory cdôü¦ôü¦ t cells are associated with limited ccr5 expression.naturally simian immunodeficiency virus (siv)-infected sooty mangabeys do not progress to aids despite high-level virus replication. we previously showed that the fraction of cd4(+)ccr5(+) t cells is lower in sooty mangabeys compared to humans and macaques. here we found that, after in vitro stimulation, sooty mangabey cd4(+) t cells fail to upregulate ccr5 and that this phenomenon is more pronounced in cd4(+) central memory t cells (t(cm) cells). cd4(+) t cell activation was similarly uncoupled ...201121706028
the trim5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus sivsme660 infection after repeated limiting-dose intrarectal challenge.it has recently been shown that polymorphism at the rhesus macaque trim5 locus can affect simian immunodeficiency virus (siv) replication. here we show that trim5 alleles can also affect acquisition of sivsme660. animals coexpressing the trim5(tfp) and trim5(cypa) alleles took significantly longer to become infected with sivsme660, but not sivmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other trim5 allele combinations. our results indicate that the trim5 ...201121734037
enhanced control of pathogenic simian immunodeficiency virus sivmac239 replication in macaques immunized with an interleukin-12 plasmid and a dna prime-viral vector boost vaccine regimen.dna priming has previously been shown to elicit augmented immune responses when administered by electroporation (ep) or codelivered with a plasmid encoding interleukin-12 (pil-12). we hypothesized that the efficacy of a dna prime and recombinant adenovirus 5 boost vaccination regimen (dna/rad5) would be improved when incorporating these vaccination strategies into the dna priming phase, as determined by pathogenic simian immunodeficiency virus sivmac239 challenge outcome. the whole sivmac239 pro ...201121734035
mutations in a dominant nef epitope of simian immunodeficiency virus diminish tcr:epitope peptide affinity but not epitope peptide:mhc class i binding.viruses like hiv and siv escape from containment by cd8(+) t lymphocytes through generating mutations that interfere with epitope peptide:mhc class i binding. however, mutations in some viral epitopes are selected for that have no impact on this binding. we explored the mechanism underlying the evolution of such epitopes by studying cd8(+) t lymphocyte recognition of a dominant nef epitope of sivmac251 in infected mamu-a*02(+) rhesus monkeys. clonal analysis of the p199ry-specific cd8(+) t lymph ...201121841125
dissecting the role of dendritic cells in simian immunodeficiency virus infection and aids.human immunodeficiency virus (hiv) infection is associated with the loss of the two principal types of dendritic cell (dc), myeloid dc (mdc) and plasmacytoid dc (pdc), but the mechanism of this loss and its relationship to aids pathogenesis remain ill-defined. the nonhuman primate is a powerful model to dissect this response for several reasons. both dc subsets have been well characterized in nonhuman primates and shown to have strikingly similar phenotypic and functional characteristics to thei ...201121717075
human and rhesus apobec3d, apobec3f, apobec3g, and apobec3h demonstrate a conserved capacity to restrict vif-deficient hiv-1.successful intracellular pathogens must evade or neutralize the innate immune defenses of their host cells and render the cellular environment permissive for replication. for example, to replicate efficiently in cd4(+) t lymphocytes, hiv-1 encodes a protein called viral infectivity factor (vif) that promotes pathogenesis by triggering degradation of the retrovirus restriction factor, apobec3g. other apobec3 proteins have been implicated in hiv-1 restriction, but the relevant repertoire remains a ...201121835787
changes in the plasma proteome follows chronic opiate administration in simian immunodeficiency virus infected rhesus macaques.background: substantive plasma proteomic changes follow lentiviral infection and disease pathobiology. we posit that such protein alterations are modified during drug abuse, further serving to affect the disease. to this end, we investigated the effect of opiate administration on the plasma proteome of indian-strain rhesus monkeys infected with simian immunodeficiency virus (siv) strain smm9. methods: whole blood was collected at 7 weeks prior to and 1.4 and 49 weeks after viral infection. viral ...201121821369
flow cytometry based identification of simian immunodeficiency virus env-specific b lymphocytes.siv infection of macaques is the most widely employed model for preclinical aids vaccine and pathogenesis research. in macaques, high-titer virus-specific antibodies are induced by infection, and antibody responses can drive evolution of viral escape variants. however, neutralizing antibodies (nabs) induced in response to sivmac239 and sivmac251 infection or immunization are generally undetectable or of low titer, and the identification and cloning of potent nabs from sivmac-infected macaques re ...201121689659
high cell-free virus load and robust autologous humoral immune responses in breast milk of simian immunodeficiency virus-infected african green monkeys.the design of immunologic interventions to prevent postnatal transmission of human immunodeficiency virus (hiv) will require identification of protective immune responses in this setting. simian immunodeficiency virus (siv)-infected rhesus monkeys (rms), a species that develops an aids-like illness following experimental infection, transmit the virus at a high rate during breastfeeding. in contrast, postnatal transmission of siv occurs rarely or not at all in natural, asymptomatic primate hosts ...201121734053
alcohol and hiv infection.alcohol abuse and human immunodeficiency virus (hiv) infection are major public health problems and frequently coexist in the same individual. although several studies have shown a significant association between alcohol consumption and the risk of being infected with hiv, it is unclear whether this association is due to behavioral and/or biomedical mechanisms. studies of hiv-infected patients are inherently limited in their ability to control for variables such as timing and dose of hiv exposur ...201021686230
loss of il-17-producing cd8 t cells during late chronic stage of pathogenic simian immunodeficiency virus infection.progressive disease caused by pathogenic siv/hiv infections is marked by systemic hyperimmune activation, immune dysregulation, and profound depletion of cd4(+) t cells in lymphoid and gastrointestinal mucosal tissues. il-17 is important for protective immunity against extracellular bacterial infections at mucosa and for maintenance of mucosal barrier. although il-17-secreting cd4 (th17) and cd8 (tc17) t cells have been reported, very little is known about the latter subset for any infectious di ...201021148794
blocking of α4β7 gut-homing integrin during acute infection leads to decreased plasma and gastrointestinal tissue viral loads in simian immunodeficiency virus-infected rhesus macaques.intravenous administration of a novel recombinant rhesus mab against the α4β7 gut-homing integrin (mab) into rhesus macaques just prior to and during acute siv infection resulted in significant decrease in plasma and gastrointestinal (gi) tissue viral load and a marked reduction in gi tissue proviral dna load as compared with control siv-infected rhesus macaques. this mab administration was associated with increases in peripheral blood naive and central memory cd4(+) t cells and maintenance of a ...201021149598
distinct host cell proteins incorporated by siv replicating in cd4+ t cells from natural disease resistant versus non-natural disease susceptible hosts.enveloped viruses including the simian immunodeficiency virus (siv) replicating within host cells acquire host proteins upon egress from the host cells. a number of studies have catalogued such host proteins, and a few have documented the potential positive and negative biological functions of such host proteins. the studies conducted herein utilized proteomic analysis to identify differences in the spectrum of host proteins acquired by a single source of siv replicating within cd4+ t cells from ...201021162735
persistence of gut mucosal innate immune defenses by enteric α-defensin expression in the simian immunodeficiency virus model of aids.gastrointestinal mucosa is an early target of hiv and a site of viral replication and severe cd4(+) t cell depletion. however, effects of hiv infection on gut mucosal innate immune defense have not been fully investigated. intestinal paneth cell-derived α-defensins constitute an integral part of the gut mucosal innate defense against microbial pathogens. using the siv-infected rhesus macaque model of aids, we examined the level of expression of rhesus enteric α-defensins (reds) in the jejunal mu ...201021178012
partial protection against siv challenge by vaccination of adenovirus and mva vectors in rhesus monkeys.this study explores the effect of priming rhesus monkeys with an ad5/35 vector expressing simian immunodeficiency virus (siv) gag and gp120, and then boosting the animals with an modified vaccinia virus ankara (mva) vector encoding the same antigens after a 2-month interval. the animals were intravenously challenged with 100 tcid50 of highly pathogenic sivmac239 virus 2 months after the booster vaccination. the priming vaccination induced robust siv-specific cell-mediated and humoral immune resp ...201019759567
sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection.worldwide, an increasing number of women use oral or injectable hormonal contraceptives. however, inadequate information is available to aid women and health care professionals in weighing the potential risks of hormonal contraceptive use in individuals living with hiv-1 or at high risk of infection. numerous epidemiological studies and challenge studies in a rhesus macaque model suggest that progesterone-based contraceptives increase the risk of hiv-1 infection in humans and simian immunodefici ...201019903932
envelope vaccination shapes viral envelope evolution following simian immunodeficiency virus infection in rhesus monkeys.the evolution of envelope mutations by replicating primate immunodeficiency viruses allows these viruses to escape from the immune pressure mediated by neutralizing antibodies. vaccine-induced anti-envelope antibody responses may accelerate and/or alter the specificity of the antibodies, thus shaping the evolution of envelope mutations in the replicating virus. to explore this possibility, we studied the neutralizing antibody response and the envelope sequences in rhesus monkeys vaccinated with ...201019906933
quantitative plasma proteomic profiling identifies the vitamin e binding protein afamin as a potential pathogenic factor in siv induced cns disease.investigating, predicting, diagnosing, and treating hiv-1-associated neurocognitive disorder (hand) has been hindered by the lack of disease-related molecular markers. in this study, plasma from rhesus monkeys (n = 6), before and after infection with simian immunodeficiency virus (siv), was profiled to obtain differential fingerprints in protein expression during siv-induced central nervous system (cns) disease. a quantitative proteomic analysis was performed by means of isobaric tag for relativ ...201019908921
nonpathogenesis of simian immunodeficiency virus infection is associated with reduced inflammation and recruitment of plasmacytoid dendritic cells to lymph nodes, not to lack of an interferon type i response, during the acute phase.divergent toll-like receptor 7 (tlr7) and tlr9 signaling has been proposed to distinguish pathogenic from nonpathogenic simian immunodeficiency virus infection in primate models. we demonstrate here that increased expression of type i interferon in pathogenic rhesus macaques compared to nonpathogenic african green monkeys was associated with the recruitment of plasmacytoid dendritic cells in the lymph nodes and the presence of an inflammatory environment early after infection, instead of a diffe ...201019939930
trafficking, persistence, and activation state of adoptively transferred allogeneic and autologous simian immunodeficiency virus-specific cd8(+) t cell clones during acute and chronic infection of rhesus macaques.despite multiple lines of evidence suggesting their involvement, the precise role of cd8(+) t cells in controlling hiv replication remains unclear. to determine whether cd8(+) t cells can limit retroviral replication in the absence of other immune responses, we transferred 1-13 x 10(9) allogeneic in vitro expanded siv-specific cd8(+) t cell clones matched for the relevant restricting mhc-i allele into rhesus macaques near the time of i.v. siv challenge. additionally, in vitro expanded autologous ...201019949089
distribution, persistence, and efficacy of adoptively transferred central and effector memory-derived autologous simian immunodeficiency virus-specific cd8+ t cell clones in rhesus macaques during acute infection.plasma viremia decreases coincident with the appearance of virus-specific cd8(+) t cells during acute hiv or siv infection. this finding, along with demonstrations of viral mutational escape from cd8(+) t cell responses and transient increase in plasma viremia after depletion of cd8(+) t cells in siv-infected monkeys strongly suggest a role for cd8(+) t cells in controlling hiv/siv. however, direct quantitative or qualitative correlates between cd8(+) t cell activity and virus control have not b ...201019949091
immunogenicity of viral vector, prime-boost siv vaccine regimens in infant rhesus macaques: attenuated vesicular stomatitis virus (vsv) and modified vaccinia ankara (mva) recombinant siv vaccines compared to live-attenuated siv.in a previously developed infant macaque model mimicking hiv infection by breast-feeding, we demonstrated that intramuscular immunization with recombinant poxvirus vaccines expressing simian immunodeficiency virus (siv) structural proteins provided partial protection against infection following oral inoculation with virulent siv. in an attempt to further increase systemic but also local antiviral immune responses at the site of viral entry, we tested the immunogenicity of different orally admini ...201019995539
preservation of memory cd4(+) t lymphocytes in breast milk of lactating rhesus monkeys during acute simian immunodeficiency virus infection.acute human immunodeficiency virus (hiv) or simian immunodeficiency virus (siv) infection is associated with a massive depletion of memory cd4(+) t lymphocytes in the gastrointestinal tract. to define the dynamics of the cd4(+) t lymphocyte subpopulations in breast milk during acute hiv or siv infection, lymphocyte populations were monitored in blood and milk of 4 mamu-a*01(+) rhesus monkeys after sivmac251 inoculation. strikingly, although the cd4(+) t lymphocytes in blood were depleted during ...201020001855
cytoskeletal proteins bound to heat-shock protein 70 may elicit resistance to simian immunodeficiency virus infection of cd4(+) t cells.this study is based on the evidence that immunization of macaques with human cd4(+) t cells elicits prevention of simian immunodeficiency virus (siv) infection. we hypothesized that heat-shock protein 70 (hsp70) isolated from cd4(+) t cells may act as a chaperone and carry the protective host proteins. two moieties of hsp70 were affinity-purified from human cd4(+) t cells; an adp preparation with hsp70-bound proteins (adp-hsp) and an atp control preparation. immunization of rhesus macaques with ...201020002211
myocarditis in cd8-depleted siv-infected rhesus macaques after short-term dual therapy with nucleoside and nucleotide reverse transcriptase inhibitors.although highly active antiretroviral therapy (haart) has dramatically reduced the morbidity and mortality associated with hiv infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (nrtis). current treatment guidelines recommend the use of haart regimens containing two nrtis for initial therapy of hiv-1 positive individuals; however, potential cardiotoxicity resultin ...201021203448
early myeloid dendritic cell dysregulation is predictive of disease progression in simian immunodeficiency virus infection.myeloid dendritic cells (mdc) are lost from blood in individuals with human immunodeficiency virus (hiv) infection but the mechanism for this loss and its relationship to disease progression are not known. we studied the mdc response in blood and lymph nodes of simian immunodeficiency virus (siv)-infected rhesus macaques with different disease outcomes. early changes in blood mdc number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable i ...201021203477
small intestine cd4+ cell reduction and enteropathy in simian/human immunodeficiency virus ks661-infected rhesus macaques in the presence of low viral load.human immunodeficiency virus type 1, simian immunodeficiency virus and simian/human immunodeficiency virus (shiv) infection generally lead to death of the host accompanied by high viraemia and profound cd4(+) t-cell depletion. shiv clone ks661-infected rhesus macaques with a high viral load set point (hvl) ultimately experience diarrhoea and wasting at 6-12 months after infection. in contrast, infected macaques with a low viral load set point (lvl) usually live asymptomatically throughout the ob ...201019889928
analysis of humoral immune responses in rhesus macaques vaccinated with attenuated sivmac239deltanef and challenged with pathogenic sivmac251.to determine the correlation between protection and humoral immune response against simian immunodeficiency virus (sivmac251), 11 macaques were immunized with live-attenuated sivmac239deltanef either intravenously or via the tonsils and exposed to sivmac251 after either 6 or 15 months along with unvaccinated controls.201020015159
aids progression is associated with the emergence of il-17-producing cells early after simian immunodeficiency virus infection.il-17 is a potent effector cytokine involved in inflammatory response and antimicrobial defense. we report that siv infection of rhesus macaques (rms) results in the emergence of il-17-expressing cells during the acute phase. this subpopulation appears at day 14 postinfection concomitantly with an increase in tgf-beta and il-18 expression. this subset, which exhibits phenotypic markers of nk t cells (nkt), rather than th17 cd4 cells, persists during the chronic phase and is higher in noncontroll ...201020018630
viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for aids.highly active antiretroviral therapy (haart) enables long-term suppression of plasma hiv-1 loads in infected persons, but low-level virus persists and rebounds following cessation of therapy. during haart, this virus resides in latently infected cells, such as resting cd4(+) t cells, and in other cell types that may support residual virus replication. therapeutic eradication will require elimination of virus from all reservoirs. we report here a comprehensive analysis of these reservoirs in flui ...201020032180
evidence of early b-cell dysregulation in simian immunodeficiency virus infection: rapid depletion of naïve and memory b-cell subsets with delayed reconstitution of the naïve b-cell population.despite eliciting a robust antibody response in humans, several studies in human immunodeficiency virus (hiv)-infected patients have demonstrated the presence of b-cell deficiencies during the chronic stage of infection. while several explanations for the hiv-induced b-cell deficit have been proposed, a clear mechanistic understanding of this loss of b-cell functionality is not known. this study utilizes simian immunodeficiency virus (siv) infection of rhesus macaques to assess b-cell population ...201020032183
efficacy of multivalent adenovirus-based vaccine against simian immunodeficiency virus challenge.the prophylactic efficacies of several multivalent replication-incompetent adenovirus serotype 5 (ad5) vaccines were examined in rhesus macaques using an intrarectal high-dose simian immunodeficiency virus sivmac239 challenge model. cohorts of mamu-a*01(+)/b*17(-) indian rhesus macaques were immunized with one of several combinations of ad5 vectors expressing gag, pol, nef, and env gp140; for comparison, a mamu-a*01(+) cohort was immunized using the ad5 vector alone. there was no sign of immunol ...201020042509
expansion of foxp3+ cd8 t cells with suppressive potential in colorectal mucosa following a pathogenic simian immunodeficiency virus infection correlates with diminished antiviral t cell response and viral control.foxp3(+)cd8(+) t cells are present at low levels in humans; however, the function of these cells is not known. in this study, we demonstrate a rapid expansion of cd25(+)foxp3(+)cd8(+) regulatory t cells (tregs) in the blood and multiple tissues following a pathogenic siv infection in rhesus macaques. the expansion was pronounced in lymphoid and colorectal mucosal tissues, preferential sites of virus replication. these cd8 tregs expressed molecules associated with immune suppressor function such ...201020053943
gut mucosal foxp3+ regulatory cd4+ t cells and nonregulatory cd4+ t cells are differentially affected by simian immunodeficiency virus infection in rhesus macaques.the gastrointestinal tract represents a major site for human and simian immunodeficiency virus (hiv and siv) replication and cd4(+) t-cell depletion. despite severe depletion of mucosal cd4(+) t cells, foxp3(+) regulatory cd4(+) t cells (t(reg)) are highly increased in the gut mucosa of chronically hiv-infected individuals and may contribute to hiv pathogenesis, either by their immunosuppressive function or as a significant target cell population for virus production. little is known about the s ...201020071575
preexisting infection with human t-cell lymphotropic virus type 2 neither exacerbates nor attenuates simian immunodeficiency virus sivmac251 infection in macaques.coinfection with human t-cell lymphotropic virus type 2 (htlv-2) and human immunodeficiency virus type 1 (hiv-1) has been reported to have either a slowed disease course or to have no effect on progression to aids. in this study, we generated a coinfection animal model and investigated whether htlv-2 could persistently infect macaques, induce a t-cell response, and impact simian immunodeficiency virus siv(mac251)-induced disease. we found that inoculation of irradiated htlv-2-infected t cells in ...201020071587
recombinant yellow fever vaccine virus 17d expressing simian immunodeficiency virus sivmac239 gag induces siv-specific cd8+ t-cell responses in rhesus macaques.here we describe a novel vaccine vector for expressing human immunodeficiency virus (hiv) antigens. we show that recombinant attenuated yellow fever vaccine virus 17d expressing simian immunodeficiency virus sivmac239 gag sequences can be used as a vector to generate siv-specific cd8(+) t-cell responses in the rhesus macaque. priming with recombinant bcg expressing siv antigens increased the frequency of these siv-specific cd8(+) t-cell responses after recombinant yf17d boosting. these recombina ...201020089645
trim5alpha modulates immunodeficiency virus control in rhesus monkeys.the cytoplasmic trim5alpha 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 trim5alpha proteins of the natural hosts. to address whether trim5alpha contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of trim5 polymorphisms in rhesus ...201020107597
local replication of simian immunodeficiency virus in the breast milk compartment of chronically-infected, lactating rhesus monkeys.breast milk transmission remains a major mode of infant hiv acquisition, yet anatomic and immunologic forces shaping virus quasispecies in milk are not well characterized. in this study, phylogenic analysis of envelope sequences of milk siv variants revealed groups of nearly identical viruses, indicating local virus production. however, comparison of the patterns and rates of ctl escape of blood and milk virus demonstrated only subtle differences between the compartments. these findings suggest ...201020122164
in vivo cd8+ t-cell suppression of siv viremia is not mediated by ctl clearance of productively infected cells.the cd8+ t-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. we studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (siv) infected rhesus macaques following cd8+ t-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with siv. as previously described, plasma viral load (vl) increased followin ...201020126442
dynamics of haplotype frequency change in a cd8+tl epitope of simian immunodeficiency virus.deep pyrosequencing of a cd8+tl epitope from the tat protein of simian immunodeficiency virus (siv) from four infected rhesus macaques carrying the restricting mhc allele (mamu-a*01) for that epitope, revealed that natural selection favoring escape mutations led to an increase in the frequency of haplotypes in the epitope region that differed from the inoculum. after 20 weeks of infection, a new sequence haplotype in the epitope region had increased to a frequency greater than 50% in each of the ...201020149896
induction of antibody-mediated neutralization in sivmac239 by a naturally acquired v3 mutation.achieving humoral immunity against human immunodeficiency virus (hiv) is a major obstacle in aids vaccine development. despite eliciting robust humoral responses to hiv, exposed hosts rarely produce broadly neutralizing antibodies. the present study utilizes simian immunodeficiency virus (siv) to identify viral epitopes that conferred antibody neutralization to clone siv/17e-cl, an in vivo variant derived from neutralization resistant sivmac239. neutralization assays using rhesus macaque monoclo ...201020153009
interleukin 18 and cardiovascular disease in hiv-1 infection: a partner in crime?cardiovascular disease has been frequent in hiv-infected patients both before and after the advent of antiretroviral therapy (haart). the pathogenic basis for the increase of cardiovascular disease, in particular myocardial lesions, may involve hiv-1 itself or other mechanisms including endothelial dysfunction, activation of proinflammatory cytokines, and changes in platelets, which lead to atherosclerotic lesions of blood vessels. in the last decade, among the proinflammatory cytokines, interle ...201020216908
high viremia is associated with high levels of in vivo major histocompatibility complex class i downregulation in rhesus macaques infected with simian immunodeficiency virus sivmac239.human and simian immunodeficiency viruses (hiv and siv) downregulate major histocompatibility complex class i (mhc-i) molecules from the surface of infected cells. although this activity is conserved across viral isolates, its importance in aids pathogenesis is not clear. we therefore developed an assay to detect the level of mhc-i expression of siv-infected cells directly ex vivo. here we show that the extent of mhc-i downregulation is greatest in sivmac239-infected macaques that never effectiv ...201020219903
peripheral blood cd4 and cd8 double-positive t cells of rhesus macaques become vulnerable to simian immunodeficiency virus by in vitro stimulation due to the induction of ccr5.in vivo simian immunodeficiency virus (siv) challenge of macaques demonstrated the earlier disappearance of cd4 and cd8 double-positive (dp) t cells than cd4 single-positive t cells, although its mechanism remains unclear. here we found that peripheral dp t cells were readily induced to express ccr5, a secondary receptor for siv, by in vitro stimulation with either concanavalin a or anti-cd3/cd28 monoclonal antibodies. activated dp t cells were more vulnerable to siv infection, indicating that t ...201020224239
identification of 81lgxgxxixw89 and 171edrw174 domains from human immunodeficiency virus type 1 vif that regulate apobec3g and apobec3f neutralizing activity.the human cytidine deaminases apobec3g (a3g) and apobec3f (a3f) potently restrict human immunodeficiency virus type 1 (hiv-1) replication, but they are neutralized by the viral protein vif. vif bridges a3g and a3f with a cullin 5 (cul5)-based e3 ubiquitin ligase and mediates their proteasomal degradation. this mechanism has been extensively studied, and several vif domains have been identified that are critical for a3g and a3f neutralization. here, we identified two additional domains. via seque ...201020335268
systemic spironucleosis in 2 immunodeficient rhesus macaques (macaca mulatta).spironucleus spp are parasites of fish and terrestrial vertebrates, including mice and turkeys, that rarely cause extraintestinal disease. two rhesus macaques (macaca mulatta) were experimentally inoculated with simian immunodeficiency virus mac251. both progressed to simian acquired immune deficiency syndrome within 1 year of inoculation and developed systemic protozoal infections in addition to common opportunistic infections, including rhesus cytomegalovirus, rhesus lymphocryptovirus, and rhe ...201020351359
autologous neutralizing antibodies to the transmitted/founder viruses emerge late after simian immunodeficiency virus sivmac251 infection of rhesus monkeys.while the simian immunodeficiency virus (siv)-infected rhesus monkey is an important animal model for human immunodeficiency virus type 1 (hiv-1) infection of humans, much remains to be learned about the evolution of the humoral immune response in this model. in hiv-1 infection, autologous neutralizing antibodies emerge 2 to 3 months after infection. however, the ontogeny of the siv-specific neutralizing antibody response in mucosally infected animals has not been defined. we characterized the k ...201020357097
depo-provera does not alter disease progression in sivmac-infected female chinese rhesus macaques.depo-provera (medroxyprogesterone acetate), a long-acting derivative of progesterone, is utilized during many nonhuman primate microbicide studies to facilitate simian immunodeficiency virus (siv) infection by thinning the vaginal epithelium. to date, the systemic effects of this steroid hormone in regard to siv/hiv pathogenesis are not well understood, but an increase in infection rates and lymphoproliferation following progesterone application has been reported. therefore, a proactive study us ...201020377424
expression, purification, crystallization and preliminary x-ray diffraction analysis of rhesus macaque cd8alphaalpha homodimer.as a t-cell co-receptor, cd8 binds to mhc class i molecules and plays a pivotal role in the activation of cytotoxic t lymphocytes. to date, structures of cd8 have been solved for two different mammals: human and mouse. the infection of rhesus macaques (macaca mulatta) by simian immunodeficiency virus (siv) is the best animal model for studying hiv. in this study, the rhesus macaque cd8 (rcd8) alphaalpha homodimer was obtained and rcd8alpha exodomain protein crystals were successfully obtained fo ...201020383016
differential cell surface expression of rhesus macaque's major histocompatibility complex class i alleles mamu-b*1703 and mamu-b*0101.the major histocompatibility complex class i allele mamu-b*17 of rhesus macaques is an elite controller of simian immunodeficiency virus (siv) infection whereas mamu-b*01 has no inhibitory effect on siv replication. the mechanism is still elusive. in this study, the so-called "missing g" in the leading peptide sequence of mamu-b*1703 allele was artificially inserted back through pcr amplification, and the new sequence was renamed as mamu-b*1703(+g). the plasmids harboring mamu-b*1703, mamu-b*170 ...201020383467
antibody-mediated protection against mucosal simian-human immunodeficiency virus challenge of macaques immunized with alphavirus replicon particles and boosted with trimeric envelope glycoprotein in mf59 adjuvant.we have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus shiv(sf162p4) following sequential immunization with alphavirus replicon particles (vrp) of a chimeric recombinant vee/sin alphavirus (derived from venezuelan equine encephalitis virus [vee] and the sindbis virus [sin]) encoding human immunodeficiency virus type 1 hiv-1(sf162) gp140deltav2 envelope (env) and trimeric env protein in mf59 adjuvant ...201020392857
variability in a dominant block to siv early reverse transcription in rhesus monkey cells predicts in vivo viral replication and time to death.while it has long been appreciated that there is considerable variability in host containment of hiv/siv replication, the determinants of that variability are not fully understood. previous studies demonstrated that the degree of permissivity of a macaque's peripheral blood mononuclear cells (pbmc) for infection with simian immunodeficiency virus (siv) in vitro predicted that animal's peak plasma virus rna levels following siv infection in vivo. the present study was conducted to define the mech ...201020416115
frequency of the major histocompatibility complex mamu-a*01 allele in experimental rhesus macaques in china.in indian rhesus macaques, the major histocompatibility complex mamu gene, especially the mamu-a*01 allele, plays an important role in simian immunodeficiency virus susceptibility and disease progression. the mamu-a*01 allele is one of the protective genes mostly being studied in simian acquired immunodeficiency syndrome.201020444001
multiple vaccine-elicited nonneutralizing antienvelope antibody activities contribute to protective efficacy by reducing both acute and chronic viremia following simian/human immunodeficiency virus shiv89.6p challenge in rhesus macaques.we have shown that following priming with replicating adenovirus type 5 host range mutant (ad5hr)-human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) recombinants, boosting with gp140 envelope protein enhances acute-phase protection against intravenous simian/human immunodeficiency virus (shiv)(89.6p) challenge compared to results with priming and no boosting or boosting with an hiv polypeptide representing the cd4 binding site of gp120. we retrospectively analyzed antibodies ...201020444898
a limited number of simian immunodeficiency virus (siv) env variants are transmitted to rhesus macaques vaginally inoculated with sivmac251.single-genome amplification (sga) and sequencing of hiv-1 rna in plasma of acutely infected humans allows the identification and enumeration of transmitted/founder viruses responsible for productive systemic infection. use of this strategy as a means for identifying transmitted viruses suggested that intrarectal simian immunodeficiency virus (siv) inoculation of macaques recapitulates key features of human rectal infection. however, no studies have used the sga strategy to identify vaginally tra ...201020463069
proton magnetic resonance spectroscopy reveals neuroprotection by oral minocycline in a nonhuman primate model of accelerated neuroaids.despite the advent of highly active anti-retroviral therapy (haart), hiv-associated neurocognitive disorders continue to be a significant problem. in efforts to understand and alleviate neurocognitive deficits associated with hiv, we used an accelerated simian immunodeficiency virus (siv) macaque model of neuroaids to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury.201020479889
the most common chinese rhesus macaque mhc class i molecule shares peptide binding repertoire with the hla-b7 supertype.of the two rhesus macaque subspecies used for aids studies, the simian immunodeficiency virus-infected indian rhesus macaque (macaca mulatta) is the most established model of hiv infection, providing both insight into pathogenesis and a system for testing novel vaccines. despite the chinese rhesus macaque potentially being a more relevant model for aids outcomes than the indian rhesus macaque, the chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility ...201020480161
lineage-specific t-cell reconstitution following in vivo cd4+ and cd8+ lymphocyte depletion in nonhuman primates.many features of t-cell homeostasis in primates are still unclear, thus limiting our understanding of aids pathogenesis, in which t-cell homeostasis is lost. here, we performed experiments of in vivo cd4(+) or cd8(+) lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (rms) and sooty mangabeys (sms). whereas rms develop aids after infection with simian immunodeficiency virus (siv), siv-infected sms are typically aids-resistant. we found that, in both species, most cd4(+) or cd8(+ ...201020484087
downregulation of robust acute type i interferon responses distinguishes nonpathogenic simian immunodeficiency virus (siv) infection of natural hosts from pathogenic siv infection of rhesus macaques.the mechanisms underlying the aids resistance of natural hosts for simian immunodeficiency virus (siv) remain unknown. recently, it was proposed that natural siv hosts avoid disease because their plasmacytoid dendritic cells (pdcs) are intrinsically unable to produce alpha interferon (ifn-alpha) in response to siv rna stimulation. however, here we show that (i) acute siv infections of natural hosts are associated with a rapid and robust type i ifn response in vivo, (ii) pdcs are the principal in ...201020484518
methamphetamine increases brain viral load and activates natural killer cells in simian immunodeficiency virus-infected monkeys.methamphetamine (meth) abuse increases risky behaviors that contribute to the spread of hiv infection. in addition, because hiv and meth independently affect physiological systems including the central nervous system, hiv-induced disease may be more severe in drug users. we investigated changes in blood and brain viral load as well as differences in immune cells in chronically simian immunodeficiency virus-infected rhesus macaques that were either administered meth or used as controls. although ...201020489154
neutralizing antibodies in siv control: co-impact with t cells.human immunodeficiency virus type 1 (hiv-1) and pathogenic simian immunodeficiency virus (siv)-infected naïve hosts experience a characteristic absence of early and potent virus-specific neutralizing antibody (nab) responses preceding establishment of persistent infection. yet conversely, we have recently shown that nabs passively immunized in rhesus macaques at early post-siv challenge are capable of playing a critical role in non-sterile viremia control with implications of antibody-enhanced a ...201020510737
limited contribution of mucosal iga to simian immunodeficiency virus (siv)-specific neutralizing antibody response and virus envelope evolution in breast milk of siv-infected, lactating rhesus monkeys.breast milk transmission of human immunodeficiency virus (hiv) remains an important mode of infant hiv acquisition. interestingly, the majority of infants remain uninfected during prolonged virus exposure via breastfeeding, raising the possibility that immune components in milk prevent mucosal virus transmission. hiv-specific antibody responses are detectable in the milk of hiv-infected women and simian immunodeficiency virus (siv)-infected monkeys; however, the role of these humoral responses i ...201020519381
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