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microbial translocation in the pathogenesis of hiv infection and aids.in pathogenic simian immunodeficiency virus (siv) and human immunodeficiency virus (hiv) infections, the translocation of microbial products from the gastrointestinal (gi) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. consistently, microbial translocation is not present in nonpathogenic siv infections of natural host species. in vivo studies demonstrated that hiv/siv-associated microbial ...201323297256
evidence for a different susceptibility of primate lentiviruses to type i interferons.type i interferons induce a complex transcriptional program that leads to a generalized antiviral response against a large panel of viruses, including human immunodeficiency virus type 1 (hiv-1). however, despite the fact that interferons negatively regulate hiv-1 ex vivo, a chronic interferon state is linked to the progression of aids and to robust viral replication, rather than protection, in vivo. to explain this apparent contradiction, we hypothesized that hiv-1 may have evolved a partial re ...201323255800
efficient mucosal transmissibility but limited pathogenicity of r5 shiv sf162p3n in chinese-origin rhesus macaques.infection of rhesus macaques (rms) of indian origin with simian immunodeficiency virus or simian-hiv (shiv) provided powerful tools to study hiv-1 transmission and disease and for testing the efficacy of novel drugs, vaccines, and prevention strategies. in developing alternative nonhuman primate aids models for the ccr5 (r5)-tropic shivsf162p3n, we characterized virus transmission and infection in chinese-origin rms.201323221980
alternative serotype adenovirus vaccine vectors elicit memory t cells with enhanced anamnestic capacity compared to ad5 vectors.the failure of the adenovirus serotype 5 (ad5) vector-based human immunodeficiency virus type 1 (hiv-1) vaccine in the step study has led to the development of adenovirus vectors derived from alternative serotypes, such as ad26, ad35, and ad48. we have recently demonstrated that vaccines using alternative-serotype ad vectors confer partial protection against stringent simian immunodeficiency virus (siv) challenges in rhesus monkeys. however, phenotypic differences between the t cell responses el ...201323152535
loss of a tyrosine-dependent trafficking motif in the simian immunodeficiency virus envelope cytoplasmic tail spares mucosal cd4 cells but does not prevent disease progression.a hallmark of pathogenic simian immunodeficiency virus (siv) and human immunodeficiency virus (hiv) infections is the rapid and near-complete depletion of mucosal cd4(+) t lymphocytes from the gastrointestinal tract. loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. here, we evaluate in rhesus macaques a novel attenuated variant of pathogenic s ...201323152518
immunogenicity of a vaccine regimen composed of simian immunodeficiency virus dna, rmva, and viral particles administered to female rhesus macaques via four different mucosal routes.a comparative evaluation of the immunity stimulated with a vaccine regimen that includes simian immunodeficiency virus (siv), interleukin 2 (il-2), and il-15 dnas, recombinant modified vaccinia virus ankara (rmva), and inactivated sivmac239 particles administered into the oral and nasal cavities, small intestine, and vagina was carried out in female rhesus macaques to determine the best route to induce diverse anti-siv immunity that may be critical to protection from siv infection and disease. a ...201323408627
preclinical evaluation of hiv eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase.even in the setting of maximally suppressive antiretroviral therapy (art), hiv persists indefinitely. several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. in this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (ido) might foster inflam ...201322924680
transcriptional profiling of experimental cd8(+) lymphocyte depletion in rhesus macaques infected with simian immunodeficiency virus sivmac239.cd8(+) t cells inhibit virus replication in siv-infected rhesus macaques. however, it is unclear to what extent the viral suppression mediated by cd8(+) t cells reflects direct killing of infected cells as opposed to indirect, noncytolytic mechanisms. in this study, we used functional genomics to investigate noncytolytic mechanisms of in vivo viral suppression mediated by cd8(+) lymphocytes. eight chronically sivmac239-infected rhesus macaques underwent cd8(+) lymphocyte depletion, and rna from ...201323097439
reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti-tumor necrosis factor treatment during primary simian immunodeficiency virus infection.human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues, and cd4⁺ t-cell loss, pathogenic processes that contribute to disease progression.201323087435
simian immunodeficiency virus interactions with macaque dendritic cells.this chapter summarizes advances in the following areas: (1) dendritic cell (dc)-mediated simian immunodeficiency virus (siv) transmission, (2) role of dcs in innate and adaptive immunity against siv, and (3) approaches to harness dc function to induce anti-siv responses. the nonhuman primate (nhp) model of human immunodeficiency virus (hiv) infection in rhesus macaques and other asian nhp species is highly relevant to advance the understanding of virus-host interactions critical for transmissio ...201322975875
systemic vaccination induces clonally diverse siv-specific cd8+ t-cell populations in systemic and mucosal compartments.an hiv-1 vaccine must elicit a clonally diverse virus-specific cd8+ t-cell response to contain mutant virus forms, and these responses must be present in mucosal tissues, which are the site of early hiv-1 replication. we show that systemic delivery of prototype vaccine vectors in rhesus monkeys induced siv (simian immunodeficiency virus)-specific cd8+ t-cell responses in systemic and mucosal compartments with comparable clonal compositions. although clonal sharing was maintained between the peri ...201322763409
tetherin upregulation in simian immunodeficiency virus-infected macaques.here we show that simian immunodeficiency virus (siv) infection of rhesus macaques results in rapid upregulation of tetherin (bst-2 or cd317) on peripheral blood lymphocytes, including the cd4(+) ccr5(+) t cell targets of virus infection, with a peak of induction that coincides with peak alpha interferon (ifn-α) levels in plasma, and that tetherin remains above baseline levels throughout chronic infection. these observations are consistent with a role for tetherin in innate immunity to immunodef ...201324109219
safety and tolerability of a live oral salmonella typhimurium vaccine candidate in siv-infected nonhuman primates.nontyphoidal salmonella (nts) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. vaccination against invasive nts disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-saharan africa. live-attenuated vaccines that mimic natural infection constitute one strategy to elicit pro ...201324099872
live attenuated rev-independent nef¯siv enhances acquisition of heterologous sivsme660 in acutely vaccinated rhesus macaques.rhesus macaques (rms) inoculated with live-attenuated rev-independent nef¯ simian immunodeficiency virus (rev-ind nef¯siv) as adults or neonates controlled viremia to undetectable levels and showed no signs of immunodeficiency over 6-8 years of follow-up. we tested the capacity of this live-attenuated virus to protect rms against pathogenic, heterologous sivsme660 challenges.201324098702
longitudinal analysis of intra-host simian immunodeficiency virus recombination in varied tissues of the rhesus macaque model for neuroaids.human immunodeficiency virus intra-host recombination has never been studied in vivo both during early infection and throughout disease progression. the cd8-depleted rhesus macaque model of neuroaids was used to investigate the impact of recombination from early infection up to the onset of neuropathology in animals inoculated with a simian immunodeficiency virus (siv) swarm. several lymphoid and non-lymphoid tissues were collected longitudinally at 21 days post-infection (p.i.), 61 days p.i. an ...201323963535
immunological and virological analyses of rhesus macaques immunized with chimpanzee adenoviruses expressing the simian immunodeficiency virus gag/tat fusion protein and challenged intrarectally with repeated low doses of sivmac.human adenovirus (adhu)-based candidate aids vaccine can provide protection from simian immunodeficiency virus (siv) transmission and disease progression. however, their potential use may be limited by widespread preexisting immunity to the vector. in contrast, preexisting immunity to chimpanzee adenoviruses (adc) is relatively rare. in this study, we utilized two regimens of prime-boost immunizations with adc serotype sad-v23 (also called adc6) and sad-v24 (also called adc7) expressing siv gag/ ...201323804645
macaque paneth cells express lymphoid chemokine cxcl13 and other antimicrobial peptides not previously described as expressed in intestinal crypts.cxcl13 is a constitutively expressed chemokine that controls migration of immune cells to lymphoid follicles. previously, we found cxcl13 mrna levels increased in rhesus macaque spleen tissues during aids. this led us to examine the levels and locations of cxcl13 by detailed in situ methods in cynomolgus macaque lymphoid and intestinal tissues. our results revealed that there were distinct localization patterns of cxcl13 mrna compared to protein in germinal centers. these patterns shifted during ...201323803902
effects of alcohol consumption on antigen-specific cellular and humoral immune responses to siv in rhesus macaques.simian immunodeficiency virus (siv) infection in macaques chronically receiving ethanol results in significantly higher plasma viral loads and more rapid progression to end-stage disease. we thus hypothesized that the increased plasma viral load in ethanol-treated, siv-infected macaques would negatively correlate with antigen-specific immune responses.201323799411
crystallization and preliminary x-ray crystallographic analysis of the rhesus macaque mhc class i molecule mamu-b*17 complexed with an immunodominant sivmac239 env epitope.long-term nonprogression during simian immunodeficiency virus (siv) infection has been strongly associated with the major histocompatibility complex (mhc) class i allele mamu-b*17. here, a complex of rhesus macaque mamu-b*17 with rhesus macaque β2-microglobulin (β2m) and an immunodominant peptide (sivmac239 env241-251; lrcndtnysgf; env lf11) derived from the siv env protein was crystallized by the hanging-drop method using peg 3350 as a precipitating agent. the crystals belonged to the primitive ...201323722842
gain-of-sensitivity mutations in a trim5-resistant primary isolate of pathogenic siv identify two independent conserved determinants of trim5α specificity.retroviral capsid recognition by trim5 blocks productive infection. rhesus macaques harbor three functionally distinct trim5 alleles: trim5α(q) , trim5α(tfp) and trim5(cypa) . despite the high degree of amino acid identity between trim5α(q) and trim5α(tfp) alleles, the q/tfp polymorphism results in the differential restriction of some primate lentiviruses, suggesting these alleles differ in how they engage these capsids. simian immunodeficiency virus of rhesus macaques (sivmac) evolved to resist ...201323675300
influence of mismatch of env sequences on vaccine protection by live attenuated simian immunodeficiency virus.vaccine/challenge experiments that utilize live attenuated strains of simian immunodeficiency virus (siv) in monkeys may be useful for elucidating what is needed from a vaccine in order to achieve protective immunity. derivatives of sivmac239 and sivmac239δnef were constructed in which env sequences were replaced with those of the heterologous strain e543; these were then used in vaccine/challenge experiments. when challenge occurred at 22 weeks, 10 of 12 monkeys exhibited apparent sterilizing i ...201323637396
no viral evolution in the lymph nodes of simian immunodeficiency virus-infected rhesus macaques during combined antiretroviral therapy.to elucidate the mode of viral persistence in primate lentivirus-infected individuals during combination antiretroviral therapy (cart), four simian immunodeficiency virus 239-infected monkeys were treated with cart for 1 year. the viral env genes prepared from total rna extracted from the mesenteric lymph nodes collected at the completion of therapy were assessed by single genome amplification. analyses of nucleotide substitutions and phylogeny revealed no viral evolution during cart.201323408611
molecular requirements for t cell recognition of n-myristoylated peptides derived from the simian immunodeficiency virus nef protein.we have recently isolated a rhesus macaque cytotoxic t cell line, 2n5.1, that specifically recognizes an n-myristoylated 5-mer peptide (c(14)-gly-gly-ala-ile-ser [c14nef5]) derived from the simian immunodeficiency virus (siv) nef protein. such c14nef5-specific t cells expand in the circulation of siv-infected monkeys, underscoring the capacity of t cells to recognize viral lipopeptides; however, the molecular basis for the lipopeptide antigen presentation remains to be elucidated. here, function ...201323097434
[experimental observation of sivmac239 chinese rhesus monkey model at sub-acute phase of aids].to observe t lymphocyte subsets and indicators of changes in viral load in sub-acute period in chinese rhesus monkey model of aids sivmac239. to explore virology related index variation in sub-acute period of the chinese rhesus monkey model of aids.201324228536
mesenchymoproliferative enteropathy associated with dual simian polyomavirus and rhesus cytomegalovirus infection in a simian immunodeficiency virus-infected rhesus macaque (macaca mulatta).opportunistic viral infections are common in simian immunodeficiency virus-infected rhesus macaques and include simian polyomavirus 40 (sv40), which causes interstitial nephritis, pneumonia, meningoencephalitis, and progressive multifocal leukoencephalopathy and rhesus cytomegalovirus (macacine herpesvirus-3), which is associated with many pathologic manifestations, including the formation of neutrophil-rich gastrointestinal masses. herein we report the findings of a simian immunodeficiency viru ...201323051916
spontaneous cervicovaginal lesions and immune cell infiltrates in nonhuman primates.nonhuman primates, particularly rhesus macaques (macaca mulatta), provide important model systems for studying human reproductive infectious diseases such as human immunodeficiency virus, human papillomavirus, and chlamydia spp. an understanding of the spectrum of spontaneous cervical disease provides essential context for interpreting experimental disease outcomes in the female reproductive tract. this retrospective study characterizes the incidence of inflammatory and/or proliferative cervicov ...201323427274
immunogenicity of repeated sendai viral vector vaccination in macaques.induction of durable cellular immune responses by vaccination is an important strategy for the control of persistent pathogen infection. viral vectors are promising vaccine tools for eliciting antigen-specific t-cell responses. repeated vaccination may contribute to durable memory t-cell induction, but anti-vector antibodies could be an obstacle to its efficacy. we previously developed a sendai virus (sev) vector vaccine and showed the potential of this vector for efficient t-cell induction in m ...201222884717
activating kir copy number variation is associated with granzyme b release by nk cells during primary simian immunodeficiency virus infection in rhesus monkeys.here we show that the number of activating killer cell immunoglobulin-like receptor (kir) copies in rhesus monkeys is associated with the extent of release of cytotoxic granules by cytolytic nk cells during primary simian immunodeficiency virus sivmac251 infection. these findings suggest that nk cells expressing high levels of activating kirs efficiently kill sivmac251-infected cells, and this efficient killing contributes to the nk cell-mediated control of replication of this virus during early ...201223015705
expression sequence tag library derived from peripheral blood mononuclear cells of the chlorocebus sabaeus.african green monkeys (agm) are amongst the most frequently used nonhuman primate models in clinical and biomedical research, nevertheless only few genomic resources exist for this species. such information would be essential for the development of dedicated new generation technologies in fundamental and pre-clinical research using this model, and would deliver new insights into primate evolution.201222726727
immunogenicity of dna vaccines encoding simian immunodeficiency virus antigen targeted to dendritic cells in rhesus macaques.targeting antigens encoded by dna vaccines to dendritic cells (dcs) in the presence of adjuvants enhances their immunogenicity and efficacy in mice.201222720025
viral vectored granulocyte-macrophage colony stimulating factor inhibits vaccine protection in an siv challenge model: protection correlates with neutralizing antibody.in a previous vaccine study, we reported significant and apparently sterilizing immunity to high-dose, mucosal, simian immunodeficiency virus (siv) quasi-species challenge. the vaccine consisted of vectors based on vesicular stomatitis virus (vsv) expressing simian immunodeficiency virus (siv) gag and env genes, a boost with propagating replicon particles expressing the same siv genes, and a second boost with vsv-based vectors. concurrent with that published study we had a parallel group of maca ...201222537983
association of major histocompatibility complex class i haplotypes with disease progression after simian immunodeficiency virus challenge in burmese rhesus macaques.nonhuman primate aids models are essential for the analysis of aids pathogenesis and the evaluation of vaccine efficacy. multiple studies on human immunodeficiency virus and simian immunodeficiency virus (siv) infection have indicated the association of major histocompatibility complex class i (mhc-i) genotypes with rapid or slow aids progression. the accumulation of macaque groups that share not only a single mhc-i allele but also an mhc-i haplotype consisting of multiple polymorphic mhc-i loci ...201222491464
efficient transmission and persistence of low-frequency sivmac251 variants in cd8-depleted rhesus macaques with different neuropathology.infection of cd8-depleted rhesus macaques with the genetically heterogeneous simian immunodeficiency virus (siv)mac251 viral swarm provides a rapid-disease model for simian acquired immune deficiency syndrome and siv-encephalitis (sive). the objective was to evaluate how the diversity of the swarm influences the initial seeding of the infection that may potentially affect disease progression. plasma, lymphoid and non-lymphoid (brain and lung) tissues were collected from two infected macaques eut ...201222302881
nonmyeloablative conditioning regimen to increase engraftment of gene-modified hematopoietic stem cells in young rhesus monkeys.immune responses to transgene products may lead to rejection of transduced cells, limiting successful gene therapy for genetic diseases. while moderate dosages of chemotherapeutic agents such as busulfan may increase hematopoietic stem cells (hsc) engraftment, they are not immune suppressive and do not abrogate immune responses to transgene products. studies focused on nonmyeloablative conditioning with busulfan ± fludarabine in a clinically relevant monkey model to induce immune suppression to ...201222294147
gag-specific cellular immunity determines in vitro viral inhibition and in vivo virologic control following simian immunodeficiency virus challenges of vaccinated rhesus monkeys.a comprehensive vaccine for human immunodeficiency virus type 1 (hiv-1) would block hiv-1 acquisition as well as durably control viral replication in breakthrough infections. recent studies have demonstrated that env is required for a vaccine to protect against acquisition of simian immunodeficiency virus (siv) in vaccinated rhesus monkeys, but the antigen requirements for virologic control remain unclear. here, we investigate whether cd8(+) t lymphocytes from vaccinated rhesus monkeys mediate v ...201222761379
sequential evolution and escape from neutralization of simian immunodeficiency virus sivsme660 clones in rhesus macaques.simian immunodeficiency virus (siv) infection of rhesus macaques has become an important surrogate model for evaluating hiv vaccine strategies. the extreme resistance to neutralizing antibody (nab) of many commonly used strains, such as sivmac251/239 and sivsme543-3, limits their potential relevance for evaluating the role of nab in vaccine protection. in contrast, sivsme660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. to evaluate the role of nab in this model ...201222696650
plasmodium inui infection reduces the efficacy of a simian immunodeficiency virus dna vaccine in a rhesus macaque model through alteration of the vaccine-induced immune response.human immunodeficiency virus type 1 and malaria are co-endemic in many areas. we evaluated the effects of plasmodium inui infection on the performance of a simian immunodeficiency virus (siv) dna vaccine. rhesus macaques were infected with p. inui by transfusion of whole blood from a persistently infected animal. animals with and animals without p. inui infection were then vaccinated 4 times with an siv dna vaccine encoding sivgag, sivpol, and sivenv. animals were subsequently challenged with th ...201222693228
electrostatic potential of human immunodeficiency virus type 2 and rhesus macaque simian immunodeficiency virus capsid proteins.human immunodeficiency virus type 2 (hiv-2) and simian immunodeficiency virus isolated from a macaque monkey (sivmac) are assumed to have originated from simian immunodeficiency virus isolated from sooty mangabey (sivsm). despite their close similarity in genome structure, hiv-2 and sivmac show different sensitivities to trim5α, a host restriction factor against retroviruses. the replication of hiv-2 strains is potently restricted by rhesus (rh) monkey trim5α, while that of sivmac strain 239 (si ...201222679444
methamphetamine and inflammatory cytokines increase neuronal na+/k+-atpase isoform 3: relevance for hiv associated neurocognitive disorders.methamphetamine (meth) abuse in conjunction with human immunodeficiency virus (hiv) exacerbates neuropathogenesis and accelerates neurocognitive impairments in the central nervous system (cns), collectively termed hiv associated neurocognitive disorders (hand). since both hiv and meth have been implicated in altering the synaptic architecture, this study focused on investigating alterations in synaptic proteins. employing a quantitative proteomics approach on synaptosomes isolated from the cauda ...201222662178
siv replication in the infected rhesus macaque is limited by the size of the preexisting th17 cell compartment.the mechanisms by which some hiv-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a portion of the observed variability. however, it has been difficult to identify host immune functions that may be present before infection and that allow resistance to lentiviral disease progression. here, we show that simian immunodeficiency virus ...201222649090
accelerated heterologous adenovirus prime-boost siv vaccine in neonatal rhesus monkeys.a pediatric human immunodeficiency virus type 1 (hiv-1) vaccine would be desirable to protect infants against hiv-1 transmission from breast-feeding. such a vaccine would need to induce protective immunity at mucosal surfaces in neonates as soon as possible after birth. recombinant adenovirus (rad) vectors have been shown to elicit potent systemic and mucosal virus-specific immune responses in adult nonhuman primates and humans, but these vectors have not previously been comprehensively studied ...201222593160
antiviral antibodies and t cells are present in the foreskin of simian immunodeficiency virus-infected rhesus macaques.no information exists regarding immune responses to human immunodeficiency virus (hiv) infection in the foreskin or glans of the human penis, although this is a key tissue for hiv transmission. to address this gap, we characterized antiviral immune responses in foreskin of male rhesus macaques (rms) inoculated with simian immunodeficiency virus (siv) strain sivmac251 by penile foreskin exposure. we found a complete population of immune cells in the foreskin and glans of normal rms, although b ce ...201222532691
envelope variable region 4 is the first target of neutralizing antibodies in early simian immunodeficiency virus mac251 infection of rhesus monkeys.a major goal of aids vaccine development is to design vaccination strategies that can elicit broad and potent protective antibodies. the initial viral targets of neutralizing antibodies (nabs) early after human or simian immunodeficiency virus (hiv/siv) infection are not known. the identification of early nab epitopes that induce protective immunity or retard the progression of disease is important for aids vaccine development. the aim of this study was to determine the env residues targeted by ...201222532675
immunization with recombinant macaque major histocompatibility complex class i and ii and human immunodeficiency virus gp140 inhibits simian-human immunodeficiency virus infection in macaques.genetic, epidemiological and experimental evidence suggest that the major histocompatibility complex (mhc) is critical in controlling human immunodeficiency virus (hiv) infection. the objectives of this study were to determine whether novel recombinant mamu mhc constructs would elicit protection against rectal challenge with heterologous simian-human immunodeficiency virus (shiv) strain sf162.p4 in rhesus macaques. mamu class i and ii gene products were linked together with hiv gp140, simian imm ...201222492918
naive t cells are dispensable for memory cd4+ t cell homeostasis in progressive simian immunodeficiency virus infection.the development of aids in chronic hiv/simian immunodeficiency virus (siv) infection has been closely linked to progressive failure of cd4(+) memory t cell (t(m)) homeostasis. cd4(+) naive t cells (t(n)) also decline in these infections, but their contribution to disease progression is less clear. we assessed the role of cd4(+) t(n) in siv pathogenesis using rhesus macaques (rms) selectively and permanently depleted of cd4(+) t(n) before siv infection. cd4(+) t(n)-depleted and cd4(+) t(n)-replet ...201222451717
enhanced pulmonary arteriopathy in simian immunodeficiency virus-infected macaques exposed to morphine.hiv-associated pulmonary arterial hypertension (pah) is likely a more prevalent noninfectious complication of aids than previously recognized. furthermore, the majority of hiv-pah cases occur in individuals with a history of intravenous drug use. in this study we used a simian immunodeficiency (siv) macaque model and a primary cell-culture system to investigate the association between drug abuse and hiv infection in hiv-pah development.201222447963
role of human trim5α in intrinsic immunity.human immunodeficiency virus (hiv) has a very narrow host range. hiv type 1 (hiv-1) does not infect old world monkeys, such as the rhesus monkey (rh). rh trim5α was identified as a factor that confers resistance, intrinsic immunity, to hiv-1 infection. unfortunately, human trim5α is almost powerless to restrict hiv-1. however, human trim5α potently restricts n-tropic murine leukemia viruses (mlv) but not b-tropic mlv, indicating that human trim5α represents the restriction factor previously desi ...201222435067
plasma gelsolin accumulates in macrophage nodules in brains of simian immunodeficiency virus infected rhesus macaques.plasma gelsolin (pgsn), an isoform 1, is secreted by various types of cells in the central nervous system (cns) and periphery, but not by the liver. pgsn circulates in blood and cerebrospinal fluid (csf); however, its concentration in csf is approximately twenty times lower than in plasma. it has been shown that several types of cells such as oligodendrocytes, neurons, and/or astrocytes contribute to the overall pool of pgsn in the cns. further, it has been postulated that pgsn plays multiple ro ...201222403026
spatial alterations between cd4(+) t follicular helper, b, and cd8(+) t cells during simian immunodeficiency virus infection: t/b cell homeostasis, activation, and potential mechanism for viral escape.hiv/siv infections induce chronic immune activation with remodeling of lymphoid architecture and hypergammaglobulinemia, although the mechanisms leading to such symptoms remain to be fully elucidated. moreover, lymph nodes have been highlighted as a predilection site for siv escape in vivo. following 20 rhesus macaques infected with sivmac239 as they progress from pre-infection to acute and chronic infection, we document for the first time, to our knowledge, the local dynamics of t follicular he ...201222387550
samhd1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.samhd1 restricts the infection of dendritic and other myeloid cells by human immunodeficiency virus type 1 (hiv-1), but in lentiviruses of the simian immunodeficiency virus of sooty mangabey (sivsm)-hiv-2 lineage, samhd1 is counteracted by the virion-packaged accessory protein vpx. here we found that samhd1 restricted infection by hydrolyzing intracellular deoxynucleoside triphosphates (dntps), lowering their concentrations to below those required for the synthesis of the viral dna by reverse tr ...201222327569
trim5α and species tropism of hiv/siv.human immunodeficiency virus type 1 (hiv-1) infects humans and chimpanzees but not old world monkeys (owms) such as the rhesus monkey (rh) and cynomolgus monkey (cm). hiv-1 efficiently enters cells of owms but encounters a block before reverse transcription. this narrow host range is attributed to a barrier in the host cell. in 2004, the screening of a rh cdna library identified tripartite motif 5α (trim5α) as a cellular antiviral factor. trim5α is one of splicing variants produced by trim5 gene ...201222291694
vaccine protection against acquisition of neutralization-resistant siv challenges in rhesus monkeys.preclinical studies of human immunodeficiency virus type 1 (hiv-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (siv) challenges in rhesus monkeys. adenovirus/poxvirus and adenovirus/adenovirus-vecto ...201222217938
dynamics of memory b-cell populations in blood, lymph nodes, and bone marrow during antiretroviral therapy and envelope boosting in simian immunodeficiency virus sivmac251-infected rhesus macaques.human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) infection causes b-cell dysregulation and the loss of memory b cells in peripheral blood mononuclear cells (pbmc). these effects are not completely reversed by antiretroviral treatment (art). to further elucidate b-cell changes during chronic siv infection and treatment, we investigated memory b-cell subpopulations and plasma cells/plasmablasts (pc/pb) in blood, bone marrow, and lymph nodes of rhesus macaques during art and u ...201222973034
partial protection of shiv-infected chinese rhesus macaques against super-infection with heterologous shiv isolate.many studies have revealed a protective effect of infection with simian immunodeficiency virus (siv) or simian-human immunodeficiency virus (shiv) against subsequent infection by a related immunodeficiency virus. however, whether a protective response can be induced by an infection with an immunodeficiency virus is still currently debated in the hiv-1 vaccine field. the aim of this study was to evaluate the protection against shiv challenge in chinese macaques that had been inoculated with shivs ...201222954309
adcc develops over time during persistent infection with live-attenuated siv and is associated with complete protection against siv(mac)251 challenge.live-attenuated strains of simian immunodeficiency virus (siv) routinely confer apparent sterilizing immunity against pathogenic siv challenge in rhesus macaques. understanding the mechanisms of protection by live-attenuated siv may provide important insights into the immune responses needed for protection against hiv-1. here we investigated the development of antibodies that are functional against neutralization-resistant siv challenge strains, and tested the hypothesis that these antibodies ar ...201222927823
distinct evolutionary pressures underlie diversity in simian immunodeficiency virus and human immunodeficiency virus lineages.simian immunodeficiency virus (siv) infection of rhesus macaques causes immune depletion and disease closely resembling human aids and is well recognized as the most relevant animal model for the human disease. experimental investigations of viral pathogenesis and vaccine protection primarily involve a limited set of related viruses originating in sooty mangabeys (sivsmm). the diversity of human immunodeficiency virus type 1 (hiv-1) has evolved in humans in about a century; in contrast, siv isol ...201223055550
loss of effector and anti-inflammatory natural killer t lymphocyte function in pathogenic simian immunodeficiency virus infection.chronic immune activation is a key determinant of aids progression in hiv-infected humans and simian immunodeficiency virus (siv)-infected macaques but is singularly absent in siv-infected natural hosts. to investigate whether natural killer t (nkt) lymphocytes contribute to the differential modulation of immune activation in aids-susceptible and aids-resistant hosts, we compared nkt function in macaques and sooty mangabeys in the absence and presence of siv infection. cynomolgus macaques had si ...201223028326
vaccine-induced cd8+ t cells control aids virus replication.developing a vaccine for human immunodeficiency virus (hiv) may be aided by a complete understanding of those rare cases in which some hiv-infected individuals control replication of the virus. most of these elite controllers express the histocompatibility alleles hla-b*57 or hla-b*27 (ref. 3). these alleles remain by far the most robust associations with low concentrations of plasma virus, yet the mechanism of control in these individuals is not entirely clear. here we vaccinate indian rhesus m ...201223023123
neutralizing capacity of monoclonal antibodies that recognize peptide sequences underlying the carbohydrates on gp41 of simian immunodeficiency virus.extensive glycosylation of the envelope spikes of human and simian immunodeficiency virus (hiv and siv) is an important factor for the resistance of these viruses to neutralization by antibodies. sivmac239 gp41 has three closely spaced sites for n-linked carbohydrate attachment. rhesus macaques experimentally infected with mutant versions of sivmac239 lacking two or three of these carbohydrate sites developed strong serum reactivity against mutated peptide sequences at the site of these glycosyl ...201222993152
high-efficiency transduction of rhesus hematopoietic repopulating cells by a modified hiv1-based lentiviral vector.human immunodeficiency virus type 1 (hiv1) vectors poorly transduce rhesus hematopoietic cells due to species-specific restriction factors, including the tripartite motif-containing 5 isoformα (trim5α) which targets the hiv1 capsid. we previously developed a chimeric hiv1 (χhiv) vector system wherein the vector genome is packaged with the simian immunodeficiency virus (siv) capsid for efficient transduction of both rhesus and human cd34(+) cells. to evaluate whether χhiv vectors could efficientl ...201222871664
risk of immunodeficiency virus infection may increase with vaccine-induced immune response.to explore the efficacy of novel complementary prime-boost immunization regimens in a nonhuman primate model for hiv infection, rhesus monkeys primed by different dna vaccines were boosted with virus-like particles (vlp) and then challenged by repeated low-dose rectal exposure to simian immunodeficiency virus (siv). characteristic of the cellular immune response after the vlp booster immunization were high numbers of siv-specific, gamma interferon-secreting cells after stimulation with inactivat ...201222811518
nk and cd4+ t cell cooperative immune responses correlate with control of disease in a macaque simian immunodeficiency virus infection model.control of infectious disease may be accomplished by successful vaccination or by complex immunologic and genetic factors favoring ag-specific multicellular immune responses. using a rhesus macaque model, we evaluated ag-specific t cell-dependent nk cell immune responses in siv-infected macaques, designated "controlling" or "noncontrolling" based on long-term chronic viremia levels, to determine whether nk cell effector functions contribute to control of siv infection. we observed that gag stimu ...201222798665
characterization of the major histocompatibility complex class i a alleles in cynomolgus macaques of vietnamese origin.cynomolgus macaques (macaca fascicularis, mafa) have emerged as an important animal model for infectious disease and transplantation research. extensive characterization of their major histocompatibility complex (mhc) polymorphism regions therefore becomes urgently required. in this study, we identified 41 mhc class i a nucleotide sequences in 34 unrelated cynomolgus macaques of vietnamese origin farmed in southern china, including eight novel mafa-a sequences. we found two sequences with perfec ...201223137320
replicating adenovirus-simian immunodeficiency virus (siv) vectors efficiently prime siv-specific systemic and mucosal immune responses by targeting myeloid dendritic cells and persisting in rectal macrophages, regardless of immunization route.although priming with replicating adenovirus type 5 host range mutant (ad5hr)-human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) recombinants, followed by hiv/siv envelope boosting, has proven highly immunogenic, resulting in protection from siv/simian-human immunodeficiency virus (shiv) challenges, ad5hr recombinant distribution, replication, and persistence have not been examined comprehensively in nonhuman primates. we utilized ad5hr-green fluorescent protein and ad5hr-siv ...201222441384
replicating adenovirus-simian immunodeficiency virus (siv) recombinant priming and envelope protein boosting elicits localized, mucosal iga immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal siv(mac251) challenge.we have shown that sequential replicating adenovirus type 5 host range mutant human immunodeficiency virus/simian immunodeficiency virus (hiv/siv) recombinant priming delivered first intranasally (i.n.) plus orally and then intratracheally (i.t.), followed by envelope protein boosting, elicits broad cellular immunity and functional, envelope-specific serum and mucosal antibodies that correlate with protection from high-dose siv and simian/human immunodeficiency virus (shiv) challenges in rhesus ...201222345466
experimental infection of cynomolgus macaques (macaca fascicularis) with human varicella-zoster virus.varicella-zoster virus (vzv) is a member of the alphaherpesvirus family and the causative agent of chickenpox and shingles. to determine the utility of cynomolgus macaques (macaca fascicularis) as a nonhuman primate model to evaluate vzv-based simian immunodeficiency virus/human immunodeficiency virus (siv/hiv) vaccines, we experimentally inoculated 10 animals with the parental oka (oka-p) strain of vzv derived from mewo or telo-rf cells. vzv dna could be detected in the lungs as late as 4 days ...201222258257
control of siv infection and subsequent induction of pandemic h1n1 immunity in rhesus macaques using an ad5 [e1-, e2b-] vector platform.anti-vector immunity mitigates immune responses induced by recombinant adenovirus vector vaccines, limiting their prime-boost capabilities. we have developed a novel gene delivery and expression platform (ad5 [e1-, e2b-]) that induces immune responses despite pre-existing and/or developed concomitant ad5 immunity. in the present study, we evaluated if this new ad5 platform could overcome the adverse condition of pre-existing ad5 immunity to induce effective immune responses in prime-boost immuni ...201223041546
in vivo selection of cd4(+) t cells transduced with a gamma-retroviral vector expressing a single-chain intrabody targeting hiv-1 tat.we evaluated the potential of an anti-human immunodeficiency virus (hiv) tat intrabody (intracellular antibody) to promote the survival of cd4(+) cells after chimeric simian immunodeficiency virus (siv)/hiv (shiv) infection in rhesus macaques. following optimization of stimulation and transduction conditions, purified cd4(+) t cells were transduced with galv-pseudotyped retroviral vectors expressing either an anti-hiv-1 tat or a control single-chain intrabody. ex vivo intrabody-gene marking was ...201222734618
increased cellular immune responses and cd4+ t-cell proliferation correlate with reduced plasma viral load in siv challenged recombinant simian varicella virus - simian immunodeficiency virus (rsvv-siv) vaccinated rhesus macaques.an effective aids vaccine remains one of the highest priorities in hiv-research. our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rsvv) vector - simian immunodeficiency virus (siv) envelope and gag genes, induced neutralizing antibodies and cellular immune responses to siv and also significantly reduced plasma viral loads following intravenous pathogenic challenge with sivmac251/cx1.201222889373
live-attenuated lentivirus immunization modulates innate immunity and inflammation while protecting rhesus macaques from vaginal simian immunodeficiency virus challenge.immunization with attenuated lentiviruses is the only reliable method of protecting rhesus macaques (rm) from vaginal challenge with pathogenic simian immunodeficiency virus (siv). cd8(+) lymphocyte depletion prior to sivmac239 vaginal challenge demonstrated that a modest, gag-specific cd8(+) t cell response induced by immunization with simian-human immunodeficiency virus 89.6 (shiv89.6) protects rm. although cd8(+) t cells are required for protection, there is no anamnestic expansion of siv-spe ...201222696662
priming t-cell responses with recombinant measles vaccine vector in a heterologous prime-boost setting in non-human primates.licensed live attenuated virus vaccines capable of expressing transgenes from other pathogens have the potential to reduce the number of childhood immunizations by eliciting robust immunity to multiple pathogens simultaneously. recombinant attenuated measles virus (rmv) derived from the edmonston zagreb vaccine strain was engineered to express simian immunodeficiency virus (siv) gag protein for the purpose of evaluating the immunogenicity of rmv as a vaccine vector in rhesus macaques. rmv-gag im ...201222732429
Evidence against Extracellular Exposure of a Highly Immunogenic Region in the C-Terminal Domain of the Simian Immunodeficiency Virus gp41 Transmembrane Protein.The generally accepted model for human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein topology includes a single membrane-spanning domain. An alternate model has been proposed which features multiple membrane-spanning domains. Consistent with the alternate model, a high percentage of HIV-1-infected individuals produce unusually robust antibody responses to a region of envelope, the so-called "Kennedy epitope," that in the conventional model should be in the cytoplasm. Here we show a ...201222072749
Impact of Vaccination on Cytotoxic T Lymphocyte Immunodominance and Cooperation against Simian Immunodeficiency Virus Replication in Rhesus Macaques.Cytotoxic T lymphocyte (CTL) responses play a central role in viral suppression in human immunodeficiency virus (HIV) infections. Prophylactic vaccination resulting in effective CTL responses after viral exposure would contribute to HIV control. It is important to know how CTL memory induction by vaccination affects postexposure CTL responses. We previously showed vaccine-based control of a simian immunodeficiency virus (SIV) challenge in a group of Burmese rhesus macaques sharing a major histoc ...201222072784
traditional chinese medicine etiology and pathogenesis of acquired immune deficiency syndrome in simian immunodeficiency virus-infected chinese rhesus macaques.to investigate the traditional chinese medicine (tcm) etiology and pathogenesis of acquired immune deficiency syndrome (aids) by 18-month observation of chinese rhesus macaques infected with simian immunodeficiency virus (siv) mac239.201223427397
breaking barriers to an aids model with macaque-tropic hiv-1 derivatives.the development of an animal model of human immunodeficiency virus type 1 (hiv-1)/aids that is suitable for preclinical testing of antiretroviral therapy, vaccines, curative strategies, and studies of pathogenesis has been hampered by the human-specific tropism of hiv-1. although simian immunodeficiency virus (siv) or hiv-1/siv chimeric viruses (shivs)-rhesus macaque models are excellent surrogates for aids research, the genetic differences between siv or shiv and hiv-1 limit their utility as mo ...201223336082
in captive rhesus macaques, cervicovaginal inflammation is common but not associated with the stable polymicrobial microbiome.vaginal inoculation of rhesus macaques (rm) with simian immunodeficiency virus (siv) has been used to study the biology of hiv transmission. although the results of vaginal siv transmission experiments could be affected by vaginal inflammation, studies to date have been conducted without regard to levels of pre-existing genital inflammation present in rm. we collected cevicovaginal secretions (cvs) from 33-36 rm during the mid menstrual cycle (day 10-20) at 2 time points approximately 8 months a ...201223285244
correlates of relative resistance against low-dose rectal simian immunodeficiency virus challenges in peripheral blood mononuclear cells of vaccinated rhesus macaques.in this study, we compared the immunogenicity and protection from repeated low-dose intrarectal sivmac251 challenge in two groups of vaccinated rms. animals were immunized with live sivmac239, which had been attenuated by a deletion of the nef sequence, or they were vaccinated twice with an e1-deleted adhu5, expressing sivmac239gag. the vaccinated animals and a cohort of unvaccinated control animals were then challenged 10 times in weekly intervals with low doses of sivmac251 given rectally. our ...201223271702
comparison of systemic and mucosal vaccination: impact on intravenous and rectal siv challenge.mucosal tissues are the primary route of transmission for most respiratory and sexually transmitted diseases, including human immunodeficiency virus. we aimed to generate strong mucosal immune responses to simian immunodeficiency virus (siv) in rhesus macaques by targeting recombinant adenovirus serotype 5 (rad5) to the lung. the immunogenicity and efficacy of aerosol (ae) vaccination was compared with intramuscular (im) delivery in either an intravenous (iv) or intrarectal (ir) siv(mac251) chal ...201222031182
Fatal Pancreatitis in Simian Immunodeficiency Virus SIVmac251-Infected Macaques Treated with 2',3'-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade.Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4(+)-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV(mac251) and treated with ART. W ...201222013040
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
Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic Basal forebrain neurons.ABSTRACT: The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiencysyndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limitingenzymes for prostaglandin s ...201222157616
Structural basis of diverse Peptide accommodation by the rhesus macaque MHC class I molecule mamu-b*17: insights into immune protection from simian immunodeficiency virus.The MHC class I molecule Mamu-B*17 has been associated with elite control of SIV infection in rhesus macaques, akin to the protective effects described for HLA-B*57 in HIV-infected individuals. In this study, we determined the crystal structures of Mamu-B*17 in complex with eight different peptides corresponding to immunodominant SIV(mac)239-derived CD8(+) T cell epitopes: HW8 (HLEVQGYW), GW10 (GSHLEVQGYW), MW9 (MHPAQTSQW), QW9 (QTSQWDDPW), FW9 (FQWMGYELW), MF8 (MRHVLEPF), IW9 (IRYPKTFGW), and I ...201122084443
increased apobec3g and apobec3f expression is associated with low viral load and prolonged survival in simian immunodeficiency virus infected rhesus monkeys.the cytidine deaminases apobec3g (a3g) and apobec3f (a3f) are innate cellular factors that inhibit replication of a number of viruses, including hiv-1. since antiviral activity of apobec3 has been mainly confirmed by in vitro data, we examined their role for disease progression in the siv/macaque model for aids.201121955401
alloantigen-based aids vaccine: revisiting a "rightfully" discarded promising strategy.this report revisits the accidental discovery that protection against simian immunodeficiency virus (siv) infection in the early successful experimental aids vaccine studies in rhesus macaques was due to antibodies directed against human leukocyte antigens (hlas). the inactivated virus vaccine approach was discarded because protection was due to the host's immune reaction against the hla acquired by siv from the human cell lines in which it was grown, rather than against antigenic determinants o ...201121876718
Vif hijacks CBF-ß to degrade APOBEC3G and promote HIV-1 infection.Restriction factors, such as the retroviral complementary DNA deaminase APOBEC3G, are cellular proteins that dominantly block virus replication. The AIDS virus, human immunodeficiency virus type 1 (HIV-1), produces the accessory factor Vif, which counteracts the host's antiviral defence by hijacking a ubiquitin ligase complex, containing CUL5, ELOC, ELOB and a RING-box protein, and targeting APOBEC3G for degradation. Here we reveal, using an affinity tag/purification mass spectrometry approach, ...201122190037
trim5α does not affect simian immunodeficiency virus siv(mac251) replication in vaccinated or unvaccinated indian rhesus macaques following intrarectal challenge exposure.trim5α is a natural resistance factor that binds retroviral capsid proteins and restricts virus replication. the b30.2/spry domain of trim5α is polymorphic in rhesus macaques, and some alleles are associated with reduced simian immunodeficiency virus (siv) siv(mac251) and siv(sme543) replication in vivo. we determined the distribution of trim5α alleles by pcr and sequence analysis of the b30.2/spry domain in a cohort of 82 macaques. thirty-nine of these macaques were mock vaccinated, 43 were vac ...201121917950
Variability of bio-clinical parameters in Chinese-origin Rhesus macaques infected with simian immunodeficiency virus: a nonhuman primate AIDS model.Although Chinese-origin Rhesus macaques (Ch RhMs) infected with simian immunodeficiency virus (SIV) have been used for many years to evaluate the efficacy of AIDS vaccines and therapeutics, the bio-clinical variability of such a nonhuman primate AIDS model was so far not established.201121850259
major histocompatibility complex class i-restricted cytotoxic t lymphocyte responses during primary simian immunodeficiency virus infection in burmese rhesus macaques.major histocompatibility complex class i (mhc-i)-restricted cd8(+) cytotoxic t lymphocyte (ctl) responses are crucial for the control of human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) replication. in particular, gag-specific ctl responses have been shown to exert strong suppressive pressure on hiv/siv replication. additionally, association of vif-specific ctl frequencies with in vitro anti-siv efficacy has been suggested recently. host mhc-i genotypes could affect th ...201121895748
distinct expression patterns of cd69 in mucosal and systemic lymphoid tissues in primary siv infection of rhesus macaques.although the intestinal tract plays a major role in early human immunodeficiency virus (hiv) infection, the role of immune activation and viral replication in intestinal tissues is not completely understood. further, increasing evidence suggests the early leukocyte activation antigen cd69 may be involved in the development or regulation of important t cell subsets, as well as a major regulatory molecule of immune responses. using the simian immunodeficiency virus (siv) rhesus macaque model, we c ...201122096538
association of activating kir copy number variation of nk cells with containment of siv replication in rhesus monkeys.while the contribution of cd8(+) cytotoxic t lymphocytes to early containment of hiv-1 spread is well established, a role for nk cells in controlling hiv-1 replication during primary infection has been uncertain. the highly polymorphic family of kir molecules expressed on nk cells can inhibit or activate these effector cells and might therefore modulate their activity against hiv-1-infected cells. in the present study, we investigated copy number variation in kir3dh loci encoding the only activa ...201122194686
TRIM5 allelic polymorphism in macaque species/populations of different geographic origins: its impact on SIV vaccine studies.Tripartite motif 5a (TRIM5a) is a potent antiretroviral immune factor present in the cytoplasm of cells of most tissue types. The rhesus macaque TRIM5 gene has been shown to display polymorphism, with different variants being divided into three groups (TRIM5(TFP), TRIM5(Q), and TRIM5(CypA)), which may have divergent retroviral effects on infection. Along with rhesus macaques, cynomolgus macaques are also used in simian immunodeficiency virus (SIV) infection studies. As a consequence, TRIM5 genot ...201121929574
association of tlr7 variants with aids-like disease and aids vaccine efficacy in rhesus macaques.in hiv infection, tlr7-triggered ifn-α production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to aids. tlr7 could also be an important mediator of vaccine efficacy. in this study, we analyzed polymorphisms in the x-linked tlr7 gene in the rhesus macaque model of aids. upon resequencing of the tlr7 gene in 36 rhesus macaques of indian origin, 12 polymorphic sites were detected. next, we identified three tigh ...201122022401
myeloid dendritic cells isolated from tissues of siv-infected rhesus macaques promote the induction of regulatory t-cells.objective:: to determine whether the ability of primary myeloid dendritic cells (mdc) to induce regulatory t cells (treg) is affected by chronic siv infection. design:: modulation of dc activity with the aim of influencing treg frequency may lead to new treatment options for hiv and strategies for vaccine development. methods:: eleven chronically-infected siv rhesus macaques were compared with four uninfected animals. immature and mature mdc were isolated from mesenteric lymph nodes and spleen b ...201122095196
targeting the vaginal mucosa with human papillomavirus pseudovirion vaccines delivering simian immunodeficiency virus dna.the majority of hiv infections occur via mucosal transmission. vaccines that induce memory t and b cells in the female genital tract may prevent the establishment and systemic dissemination of hiv. we tested the immunogenicity of a vaccine that uses human papillomavirus (hpv)-based gene transfer vectors, also called pseudovirions (psvs), to deliver siv genes to the vaginal epithelium. our findings demonstrate that this vaccine platform induces gene expression in the genital tract in both cynomol ...201122174446
Expression of Structural Proteins in Human Female and Male Genital Epithelia and Implications for Sexually Transmitted Infections.Men and women differ in their susceptibility to sexually transmittable infections (STI) such as human immunodeficiency virus (HIV). However, a paucity of published information regarding the tissue structure of the human genital tract has limited our understanding of these gender differences. We collected cervical, vaginal, and penile tissues from human adult donors. Tissues were prepared with H&E stains or immunofluorescence labeling of epithelial cell proteins and analyzed for structural charac ...201121976595
Diversity of TRIM5a and TRIMCyp sequences in cynomolgus macaques from different geographical origins.The TRIM5a restriction factor can protect some species of monkeys, but not humans, from HIV infection. It has also emerged that some monkeys have a cyclophilin A domain retrotransposed into the TRIM5 locus resulting in the expression of a TRIMCyp protein with anti-retroviral activity. A high degree of sequence variation in the primate TRIM5 gene has been reported that varies between populations of rhesus macaques, a widely used non-human primate model of HIV/AIDS, and recently shown to correlate ...201122124667
durable mucosal simian immunodeficiency virus-specific effector memory t lymphocyte responses elicited by recombinant adenovirus vectors in rhesus monkeys.the induction of potent and durable cellular immune responses in both peripheral and mucosal tissues may be important for the development of effective vaccines against human immunodeficiency virus type 1 and other pathogens. in particular, effector responses at mucosal surfaces may be critical to respond rapidly to incoming mucosal pathogens. here we report that intramuscular injection of nonreplicating recombinant adenovirus (rad) vectors into rhesus monkeys induced remarkably durable simian im ...201121917969
The simian immunodeficiency virus targets central cell cycle functions through transcriptional repression in vivo.A massive and selective loss of CD4+ memory T cells occurs during the acute phase of immunodeficiency virus infections. The mechanism of this depletion is poorly understood but constitutes a key event with implications for progression. We assessed gene expression of purified T cells in Rhesus Macaques during acute SIVmac239 infection in order to define mechanisms of pathogenesis. We observe a general transcriptional program of over 1,600 interferon-stimulated genes induced in all T cells by the ...201122043290
evidence for an increased risk of transmission of simian immunodeficiency virus and malaria in a rhesus macaque coinfection model.in sub-saharan africa, hiv-1 infection frequently occurs in the context of other coinfecting pathogens, most importantly, mycobacterium tuberculosis and malaria parasites. the consequences are often devastating, resulting in enhanced morbidity and mortality. due to the large number of confounding factors influencing pathogenesis in coinfected people, we sought to develop a nonhuman primate model of simian immunodeficiency virus (siv)-malaria coinfection. in sub-saharan africa, plasmodium falcipa ...201121917966
correlation between cd4+ t-cell loss and gag-specific t cells in different intestinal sites of chronically siv-infected rhesus monkeys.to determine the loss of cd4+ t cells and virus-specific cytotoxic t cells (ctl) in different mucosal sites of rhesus monkeys infected with simian immunodeficiency virus (siv).201121192228
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