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exposure to siv in utero results in reduced viral loads and altered responsiveness to postnatal challenge.hiv disease progression appears to be driven by increased immune activation. given observations that fetal exposure to infectious pathogens in utero can result in reduced immune responses, or tolerance, to those pathogens postnatally, we hypothesized that fetal exposure to hiv may render the fetus tolerant to the virus, thus reducing damage caused by immune activation during infection later in life. to test this hypothesis, fetal rhesus macaques (macaca mulatta) were injected with the attenuated ...201526268312
breakthrough of siv strain sme660 challenge in siv strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses.although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nabs) against the challenge virus will prevent infection. this paradigm is based on a series of studies in which passive transfer of hiv-specific nabs protected rhesus macaques (rms) from subsequent mucosal challenge with a chimeric human/simian immunod ...201526261312
elite control, gut cd4 t cell sparing, and enhanced mucosal t cell responses in macaca nemestrina infected by a simian immunodeficiency virus lacking a gp41 trafficking motif.deletion of gly-720 and tyr-721 from a highly conserved gyxxø trafficking signal in the sivmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed δgy, leads to a striking perturbation in pathogenesis in rhesus macaques (macaca mulatta). infected macaques develop immune activation and progress to aids, but with only limited and transient infection of intestinal cd4(+) t cells and an absence of microbial translocation. here we evaluated δgy in pig-tailed macaques (macaca nemestr ...201526223646
reduced simian immunodeficiency virus replication in macrophages of sooty mangabeys is associated with increased expression of host restriction factors.macrophages are target cells of hiv/siv infection that may play a role in aids pathogenesis and contribute to the long-lived reservoir of latently infected cells during antiretroviral therapy (art). in previous work, we and others have shown that during pathogenic siv infection of rhesus macaques (rms), rapid disease progression is associated with high levels of in vivo macrophage infection. in contrast, during nonpathogenic siv infection of sooty mangabeys (sms), neither spontaneous nor experim ...201526202248
rhesus immune responses to siv gag expressed by recombinant bcg vectors are independent from pre-existing mycobacterial immunity.a recombinant mycobacterium bovis bcg (rbcg) vector expressing hiv transgenes is an attractive candidate as a dual vaccine against hiv and tb. however, pre-existing immune responses to mycobacteria may influence immune responses to rbcg. we analyzed data from a rhesus rbcg trial to determine the effect of pre-existing mycobacterial immune responses on the vaccine-induced responses to the vector and expressed transgene.201526192357
rapid development of gp120-focused neutralizing b cell responses during acute simian immunodeficiency virus infection of african green monkeys.the initial phases of acute human immunodeficiency virus type 1 (hiv-1) infection may be critical for development of effective envelope (env)-specific antibodies capable of impeding the establishment of the latent pool of hiv-1-infected cd4(+) t cells, preventing virus-induced immune hyperactivation to limit disease progression and blocking vertical virus transmission. however, the initial systemic hiv-1 env-specific antibody response targets gp41 epitopes and fails to control acute-phase viremi ...201526157116
high expression levels of blys/baff by blood dendritic cells and granulocytes are associated with b-cell dysregulation in siv-infected rhesus macaques.dendritic cells (dcs) modulate b-cell survival and differentiation, mainly through production of growth factors such as b lymphocyte stimulator (blys/baff). in recent longitudinal studies involving hiv-1-infected individuals with different rates of disease progression, we have shown that dcs were altered in number and phenotype in the context of hiv-1 disease progression and b-cell dysregulations were associated with increased blys/baff expression in plasma and by blood myeloid dcs (mdcs) in rap ...201526107380
cocrystal structures of antibody n60-i3 and antibody jr4 in complex with gp120 define more cluster a epitopes involved in effective antibody-dependent effector function against hiv-1.accumulating evidence indicates a role for fc receptor (fcr)-mediated effector functions of antibodies, including antibody-dependent cell-mediated cytotoxicity (adcc), in prevention of human immunodeficiency virus type 1 (hiv-1) acquisition and in postinfection control of viremia. consequently, an understanding of the molecular basis for env epitopes that constitute effective adcc targets is of fundamental interest for humoral anti-hiv-1 immunity and for hiv-1 vaccine design. a substantial porti ...201526085162
differential impact of in vivo cd8+ t lymphocyte depletion in controller versus progressor simian immunodeficiency virus-infected macaques.numerous studies have demonstrated that cd8(+) t lymphocytes suppress virus replication during human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) infection. however, the mechanisms underlying this activity of t cells remain incompletely understood. here, we conducted cd8(+) t lymphocyte depletion in 15 rhesus macaques (rms) infected intravenously (i.v.) with sivmac239. at day 70 postinfection, the animals (10 progressors with high viremia and 5 controllers with low viremia) w ...201526063417
tracking the emergence of host-specific simian immunodeficiency virus env and nef populations reveals nef early adaptation and convergent evolution in brain of naturally progressing rhesus macaques.while a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (cns) has not yet been reached, the simian immunodeficiency virus (siv)-infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (hiv) intrahost evolution and neuropathogenesis. the evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintena ...201526041280
high immune activation and abnormal expression of cytokines contribute to death of shiv89.6-infected chinese rhesus macaques.chinese rhesus macaques (crms) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) and for vaccine research. shiv89.6 has been reported to be an attenuated virus because, in most cases, shiv89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. after two serial passages in vivo, shiv (shiv-89.6p) induces cd4 lymphopenia and an aids-like di ...201526036562
characterization and implementation of a diverse simian immunodeficiency virus sivsm envelope panel in the assessment of neutralizing antibody breadth elicited in rhesus macaques by multimodal vaccines expressing the sivmac239 envelope.antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (hiv-1) vaccine. to this end, preclinical simian immunodeficiency virus (siv)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. however, these trials often rely on a limited selection of siv strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. to ...201526018167
two-year follow-up of macaques developing intermittent control of the human immunodeficiency virus homolog simian immunodeficiency virus sivmac251 in the chronic phase of infection.off-therapy control of viremia by hiv-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. we previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically ...201525972547
activated cd4+ccr5+ t cells in the rectum predict increased siv acquisition in sivgag/tat-vaccinated rhesus macaques.an effective t-cell-based aids vaccine should induce strong hiv-specific cd8(+) t cells in mucosal tissues without increasing the availability of target cells for the virus. here, we evaluated five immunization strategies that include human adenovirus-5 (adhu5), chimpanzee adenovirus-6 (adc6) or -7 (adc7), vaccinia virus (vv), and dna given by electroporation (dna/ep), all expressing simian immunodeficiency virus group specific antigen/transactivator of transcription (siv(mac239gag/tat)). five g ...201525550504
vaccine induction of lymph node-resident simian immunodeficiency virus env-specific t follicular helper cells in rhesus macaques.measurement of ag-specific t follicular helper (tfh) cell activity in rhesus macaques has not previously been reported. given that rhesus macaques are the animal model of choice for evaluating protective efficacy of hiv/siv vaccine candidates and that tfh cells play a pivotal role in aiding b cell maturation, quantifying vaccine induction of hiv/siv-specific tfh cells would greatly benefit vaccine development. in this study, we quantified siv env-specific il-21-producing tfh cells for the first ...201626773147
utilizing a tlr5-adjuvanted cytomegalovirus as a lentiviral vaccine in the nonhuman primate model for aids.despite tremendous progress in our understanding of human immunodeficiency virus (hiv) natural history and advances in hiv treatment, there is neither an approved vaccine nor a cure for infection. here, we describe the development and characterization of a novel replicating vaccine vector utilizing cytomegalovirus (cmv) and a tlr5 adjuvant. after partial truncation of the central, immunodominant hypervariable domain, flagellin (flic) from salmonella was cloned downstream of a codon optimized gag ...201627182601
infection of rhesus macaques with a pool of simian immunodeficiency virus with the envelope genes from acute hiv-1 infections.new simian-human immunodeficiency chimeric viruses with an hiv-1 env (shivenv) are critical for studies on hiv pathogenesis, vaccine development, and microbicide testing. macaques are typically exposed to single ccr5-using shivenv which in most instances does not reflect the conditions during acute/early hiv infection (ahi) in humans. instead of individual and serial testing new shiv constructs, a pool of shivenv_b derived from 16 acute hiv-1 infections were constructed using a novel yeast-based ...201627906032
breadth and magnitude of antigen-specific antibody responses in the control of plasma viremia in simian immunodeficiency virus infected macaques.increasing evidence suggests an unexpected potential for non-neutralizing antibodies to prevent hiv infection. consequently, identification of functional linear b-cell epitopes for hiv are important for developing preventative and therapeutic strategies. we therefore explored the role of antigen-specific immune responses in controlling plasma viremia in siv infected rhesus macaques.201627903274
analysis of simian immunodeficiency virus-specific cd8+ t-cells in rhesus macaques by peptide-mhc-i tetramer staining.peptide-major histocompatibility complex class i (pmhc-i) tetramers have been an invaluable tool to study cd8(+) t-cell responses. because these reagents directly bind to t-cell receptors on the surface of cd8(+) t-lymphocytes, fluorochrome-labeled pmhc-i tetramers enable the accurate detection of antigen (ag)-specific cd8(+) t-cells without the need for in vitro re-stimulation. moreover, when combined with multi-color flow cytometry, pmhc-i tetramer staining can reveal key aspects of ag-specifi ...201628060314
simian immunodeficiency virus confounds t follicular helper t cells and the germinal centre.yamamoto et al. have studied t follicular helper (tfh) and germinal centre (gc) responses after infection of rhesus macaques (rm) infected with simian immunodeficiency virus (siv). in this study the authors examined the behaviour of tfh, reproducing infection-associated tfh accumulation and their association with the quality of antibody responses against cross-clade viral epitopes. the authors correlate tfhil4 and cd154 expression with superior antibody responses. accumulation of tfh was accompa ...201628149882
siv infection facilitates mycobacterium tuberculosis infection of rhesus macaques.tuberculosis (tb) is a common opportunistic infection and the leading cause of death for human immunodeficiency virus (hiv)-infected patients. thus, it is necessary to understand the pathogenetic interactions between m.tb and hiv infection. in this study, we examined m.tb and/or simian immunodeficiency virus (siv) infection of chinese rhesus macaques. while there was little evidence that m.tb enhanced siv infection of macaques, siv could facilitate m.tb infection as demonstrated by x-rays, patho ...201628133458
chronic binge alcohol administration impairs glucose-insulin dynamics and decreases adiponectin in asymptomatic simian immunodeficiency virus-infected macaques.alcohol use disorders (auds) frequently exist among persons living with hiv/aids. chronic alcohol consumption, hiv infection, and antiretroviral therapy (art) are independently associated with impairments in glucose-insulin dynamics. previous studies from our laboratory have shown that chronic binge alcohol (cba) administration decreases body mass index, attenuates weight gain, and accentuates skeletal muscle wasting at end-stage disease in non-art-treated simian immunodeficiency virus (siv)-inf ...201627605560
simian immunodeficiency virus-producing cells in follicles are partially suppressed by cd8+ cells in vivo.human immunodeficiency virus (hiv)- and simian immunodeficiency virus (siv)-specific cd8(+) t cells are typically largely excluded from lymphoid b cell follicles, where hiv- and siv-producing cells are most highly concentrated, indicating that b cell follicles are somewhat of an immunoprivileged site. to gain insights into virus-specific follicular cd8(+) t cells, we determined the location and phenotype of follicular siv-specific cd8(+) t cells in situ, the local relationship of these cells to ...201627707919
magnitude and quality of cytokine and chemokine storm during acute infection distinguish nonprogressive and progressive simian immunodeficiency virus infections of nonhuman primates.acute human immunodeficiency virus (hiv) infection represents a period of intense immune perturbation and activation of the host immune system. study of the eclipse and viral expansion phases of infection is difficult in humans, but studies in nonprogressive and progressive nonhuman primate (nhp) infection models can provide significant insight into critical events occurring during this time. cytokines, chemokines, and other soluble immune factors were measured in longitudinal samples from rhesu ...201627630228
vif proteins from diverse human immunodeficiency virus/simian immunodeficiency virus lineages have distinct binding sites in a3c.lentiviruses have evolved the vif protein to counteract apobec3 (a3) restriction factors by targeting them for proteasomal degradation. previous studies have identified important residues in the interface of human immunodeficiency virus type 1 (hiv-1) vif and human apobec3c (ha3c) or human apobec3f (ha3f). however, the interaction between primate a3c proteins and hiv-1 vif or natural hiv-1 vif variants is still poorly understood. here, we report that hiv-1 vif is inactive against a3cs of rhesus ...201627581978
immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of hiv infection.sulfonamide hypersensitivity has a high incidence in hiv infection and correlates with low cd4+ counts, but the mechanisms are not understood. the aims of this study were to determine whether trimethoprim/sulfamethoxazole (tmp/smx) led to smx adduct formation, immunogenicity, or signs of drug hypersensitivity in siv-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or smx disposition were predictive of drug immunogenicity.201627565715
reproducing sivδnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines.vaccination with sivmac239δnef provides robust protection against subsequent challenge with wild-type simian immunodeficiency virus (siv), but safety issues have precluded designing an hiv-1 vaccine based on a live-attenuated virus concept. safe immunogens and adjuvants that could reproduce identified immune correlates of sivmac239δnef protection therefore offer an alternative path for development of an hiv vaccine. here we describe siv envelope trimeric gp41 (gp41t) immunogens based on a protec ...201627428745
loss of cerebellar neurons in the progression of lentiviral disease: effects of cns-permeant antiretroviral therapy.the majority of investigations on hiv-associated neurocognitive disorders (hand) neglect the cerebellum in spite of emerging evidence for its role in higher cognitive functions and dysfunctions in common neurodegenerative diseases.201627737697
dna prime-boost vaccine regimen to increase breadth, magnitude, and cytotoxicity of the cellular immune responses to subdominant gag epitopes of simian immunodeficiency virus and hiv.hiv sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the hiv proteome are hurdles in the development of an effective aids vaccine. an hiv-derived conserved element (ce) p24(gag) plasmid dna (pdna) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. by homology to the hiv immunogen, seven ce were identified in siv p27(gag) analysis of 31 rhesus macaques vaccinated with full- ...201627733554
comparative analysis of immune activation markers of cd8(+) t cells in lymph nodes of different origins in siv-infected chinese rhesus macaques.altered t-cell homeostasis, such as expansion of cd8(+) t cells to the secondary lymphatic compartments, has been suggested as a mechanism of hiv/simian immunodeficiency virus (siv)-pathogenesis. however, the role of immune activation of cd8(+) t cells in the cd4/cd8 turnover and viral replication in these tissues is not completely understood. in this study, we compared the expression of immune activation markers (cd69 and hla-dr) on cd8(+) t cells in the peripheral blood and lymph nodes (lns) o ...201627708644
trim5α resistance escape mutations in the capsid are transferable between simian immunodeficiency virus strains.trim5α polymorphism limits and complicates the use of simian immunodeficiency virus (siv) for evaluation of human immunodeficiency virus (hiv) vaccine strategies in rhesus macaques. we previously reported that the trim5α-sensitive siv from sooty mangabeys (sivsm) clone sivsme543-3 acquired amino acid substitutions in the capsid that overcame trim5α restriction when it was passaged in rhesus macaques expressing restrictive trim5α alleles. here we generated trim5α-resistant clones of the related s ...201627681142
cd8(+) lymphocytes are required for maintaining viral suppression in siv-infected macaques treated with short-term antiretroviral therapy.infection with hiv persists despite suppressive antiretroviral therapy (art), and treatment interruption results in rapid viral rebound. antibody-mediated cd8(+) lymphocyte depletion in simian immunodeficiency virus (siv)-infected rhesus macaques (rms) shows that these cells contribute to viral control in untreated animals. however, the contribution of cd8(+) lymphocytes to maintaining viral suppression under art remains unknown. here, we have shown that in siv-infected rms treated with short-te ...201627653601
adoptive transfer of engineered rhesus simian immunodeficiency virus-specific cd8+ t cells reduces the number of transmitted/founder viruses established in rhesus macaques.aids virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from cd4(+) t-cell infection. one likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. to test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large ...201627558423
divergent annexin a1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during siv infection.hiv-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. annexin a1 (anxa1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (siv) infection. gene expression of anxa1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of siv infection and compared with siv-ne ...201627484833
induction of th1-biased t follicular helper (tfh) cells in lymphoid tissues during chronic simian immunodeficiency virus infection defines functionally distinct germinal center tfh cells.chronic hiv infection is associated with accumulation of germinal center (gc) t follicular helper (tfh) cells in the lymphoid tissue. the gc tfh cells can be heterogeneous based on the expression of chemokine receptors associated with t helper lineages, such as cxcr3 (th1), ccr4 (th2), and ccr6 (th17). however, the heterogeneous nature of gc tfh cells in the lymphoid tissue and its association with viral persistence and ab production during chronic siv/hiv infection are not known. to address thi ...201627481845
characterization of simian immunodeficiency virus variants anatomically compartmentalized in plasma and milk in chronically infected african green monkeys.unlike human immunodeficiency virus type 1 (hiv-1)-infected humans, african-origin, natural simian immunodeficiency virus (siv) hosts, such as african green monkeys (agms), sustain nonpathogenic siv infections and rarely vertically transmit siv to their infants. interestingly, chronically siv-infected agms have anatomically compartmentalized siv variants in plasma and milk, whereas humans and siv-infected rhesus monkeys (rms), asian-origin nonnatural siv hosts, do not exhibit this compartmentali ...201627466415
virus-like particles displaying trimeric simian immunodeficiency virus (siv) envelope gp160 enhance the breadth of dna/modified vaccinia virus ankara siv vaccine-induced antibody responses in rhesus macaques.the encouraging results of the rv144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (hiv) vaccine modalities as a strategy to induce protective immunity. because vaccine-induced protective immunity is critically determined by hiv envelope (env) conformation, significant efforts are directed toward generating soluble trimeric env immunogens that assume native structures. using the simian immunodeficiency virus (siv)-macaque model, we tested the im ...201627466414
association of lymph-node antigens with lower gag-specific central-memory and higher env-specific effector-memory cd8(+) t-cell frequencies in a macaque aids model.virus-specific cd8(+) t cells exert strong suppressive pressure on human/simian immunodeficiency virus (hiv/siv) replication. these responses have been intensively examined in peripheral blood mononuclear cells (pbmcs) but not fully analyzed in lymph nodes (lns), where interaction between cd8(+) t cells and hiv/siv-infected cells occurs. here, we investigated target antigen specificity of cd8(+) t cells in lns in a macaque aids model. analysis of virus antigen-specific cd8(+) t-cell responses in ...201627452272
relationship between vaccine-induced antibody capture of infectious virus and infection outcomes following repeated low-dose rectal challenges with simian immunodeficiency virus sivmac251.antibodies are known to enhance in vitro infection by human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv). we measured the ability of antibodies induced by alvac-siv/gp120 vaccination, given with alum or mf59 adjuvant, to capture infectious sivmac251 and determined the association between capture and infection outcomes following low-dose, repeated rectal challenge of rhesus macaques. we found that capture correlated with the number of transmitted/founder (t/f) variants tha ...201627440881
chemokine-adjuvanted electroporated dna vaccine induces substantial protection from simian immunodeficiency virus vaginal challenge.there have been encouraging results for the development of an effective hiv vaccine. however, many questions remain regarding the quality of immune responses and the role of mucosal antibodies. we addressed some of these issues by using a simian immunodeficiency virus (siv) dna vaccine adjuvanted with plasmid-expressed mucosal chemokines combined with an intravaginal siv challenge in rhesus macaque (rhm) model. we previously reported on the ability of ccr9 and ccr10 ligand (l) adjuvants to enhan ...201625943275
derivation and characterization of pathogenic transmitted/founder molecular clones from simian immunodeficiency virus sivsme660 and sivmac251 following mucosal infection.currently available simian immunodeficiency virus (siv) infectious molecular clones (imcs) and isolates used in nonhuman primate (nhp) models of aids were originally derived from infected macaques during chronic infection or end stage disease and may not authentically recapitulate features of transmitted/founder (t/f) genomes that are of particular interest in transmission, pathogenesis, prevention, and treatment studies. we therefore generated and characterized t/f imcs from genetically and bio ...201627412591
envelope-specific b-cell populations in african green monkeys chronically infected with simian immunodeficiency virus.african green monkeys (agms) are natural primate hosts of simian immunodeficiency virus (siv). interestingly, features of the envelope-specific antibody responses in siv-infected agms are distinct from that of hiv-infected humans and siv-infected rhesus monkeys, including gp120-focused responses and rapid development of autologous neutralization. yet, the lack of genetic tools to evaluate b-cell lineages hinders potential use of this unique non-human primate model for hiv vaccine development. he ...201627381634
vaccine-elicited mucosal and systemic antibody responses are associated with reduced simian immunodeficiency viremia in infant rhesus macaques.despite significant progress in reducing peripartum mother-to-child transmission (mtct) of human immunodeficiency virus (hiv) with antiretroviral therapy (art), continued access to art throughout the breastfeeding period is still a limiting factor, and breast milk exposure to hiv accounts for up to 44% of mtct. as abstinence from breastfeeding is not recommended, alternative means are needed to prevent mtct of hiv. we have previously shown that oral vaccination at birth with live attenuated myco ...201627252535
envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance cd4 binding and replication in rhesus macaques.most simian-human immunodeficiency viruses (shivs) bearing envelope (env) glycoproteins from primary hiv-1 strains fail to infect rhesus macaques (rms). we hypothesized that inefficient env binding to rhesus cd4 (rhcd4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus env residues at position 375, which resides at a critical location in the cd4-binding pocket and is under strong positive evolutionary pressure across the br ...201627247400
adjuvant-dependent innate and adaptive immune signatures of risk of sivmac251 acquisition.a recombinant vaccine containing aventis pasteur's canarypox vector (alvac)-hiv and gp120 alum decreased the risk of hiv acquisition in the rv144 vaccine trial. the substitution of alum with the more immunogenic mf59 adjuvant is under consideration for the next efficacy human trial. we found here that an alvac-simian immunodeficiency virus (siv) and gp120 alum (alvac-siv + gp120) equivalent vaccine, but not an alvac-siv + gp120 mf59 vaccine, was efficacious in delaying the onset of sivmac251 in ...201627239761
initiation of antiretroviral therapy restores cd4+ t memory stem cell homeostasis in simian immunodeficiency virus-infected macaques.treatment of human immunodeficiency virus (hiv) infection with antiretroviral therapy (art) has significantly improved prognosis. unfortunately, interruption of art almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. based on their longevity and proliferative potential, cd4(+) t memory stem cells (tscm) have been proposed as an important site of hiv persistence. in a previous study, we found that in simian immunodeficiency virus (siv)-infected ...201627170752
biphasic cd8+ t-cell defense in simian immunodeficiency virus control by acute-phase passive neutralizing antibody immunization.identifying human immunodeficiency virus type 1 (hiv-1) control mechanisms by neutralizing antibodies (nabs) is critical for anti-hiv-1 strategies. recent in vivo studies on animals infected with simian immunodeficiency virus (siv) and related viruses have shown the efficacy of postinfection nab passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. here, we describe siv control in macaques showing biphasic cd8(+ ...201627122584
evolution of neuroadaptation in the periphery and purifying selection in the brain contribute to compartmentalization of simian immunodeficiency virus (siv) in the brains of rhesus macaques with siv-associated encephalitis.the emergence of a distinct subpopulation of human or simian immunodeficiency virus (hiv/siv) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to aids-related central nervous system (cns) neuropathology. however, the exact evolutionary mechanism responsible for hiv/siv brain compartmentalization has not been thoroughly investigated. using extensive viral sampling from several different peripheral tissues and cell types and from three distinct region ...201627122578
chronic δ(9)-tetrahydrocannabinol administration reduces ige(+)b cells but unlikely enhances pathogenic sivmac251 infection in male rhesus macaques of chinese origin.delta9-tetrahydrocannabinol (δ(9)-thc) is the major psychoactive component of the cannabis plant. δ(9)-thc has been used in the active ingredient of marinol as an appetite stimulant for aids patients. its impact on progression of hiv-1 infection, however, remains debatable. previous studies indicated that δ(9)-thc administration enhanced hiv-1 infection in hupbl-scid mice but seemingly decreased early mortality in simian immunodeficiency virus (siv) infected male indian-derived rhesus macaques. ...201627109234
disrupted homeostatic cytokines expression in secondary lymph organs during hiv infection.research has firmly established that infection by human immunodeficiency virus (hiv) leads to structural disruption in secondary lymph organs (slos) and that il-7 expression by slos is downregulated in simian immunodeficiency virus (siv)-infected rhesus macaques. however, the foregoing has not been demonstrated in hiv-infected patients. as well, slo-produced chemokines and cytokines, other than il-7, have not been tested. in this study, slos in hiv-infected patients exhibit decreased levels of l ...201627011165
strong, but age-dependent, protection elicited by a deoxyribonucleic acid/modified vaccinia ankara simian immunodeficiency virus vaccine.background.  in this study, we analyzed the protective efficacy of a simian immunodeficiency virus (siv) macaque 239 (sivmac239) analogue of the clinically tested govx-b11 deoxyribonucleic acid (dna)/modified vaccinia ankara (mva) human immunodeficiency virus vaccine. methods.  the tested vaccine used a dna immunogen mutated to mimic the human vaccine and a regimen with dna deliveries at weeks 0 and 8 and mva deliveries at weeks 16 and 32. twelve weekly rectal challenges with 0.3 animal infectio ...201627006959
effects of fecal microbial transplantation on microbiome and immunity in simian immunodeficiency virus-infected macaques.an altered intestinal microbiome during chronic human immunodeficiency virus (hiv) infection is associated with mucosal dysfunction, inflammation, and disease progression. we performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (fmt) as a potential therapeutic in hiv-infected individuals. antiretroviral-treated, chronically simian immunodeficiency virus (siv)-infected rhesus macaques received antibiotics followed by fmt. the greatest microbiota shift ...201626937040
longitudinal examination of the intestinal lamina propria cellular compartment of simian immunodeficiency virus-infected rhesus macaques provides broader and deeper insights into the link between aberrant microrna expression and persistent immune activation.chronic immune activation/inflammation driven by factors like microbial translocation is a key determinant of human immunodeficiency virus/simian immunodeficiency virus (hiv/siv) disease progression. although extensive research on inflammation has focused on studying protein regulators, increasing evidence suggests a critical role for micrornas (mirnas) in regulating several aspects of the immune/inflammatory response and immune cell proliferation, differentiation, and activation. to understand ...201626937033
mucosa-associated invariant t cells are systemically depleted in simian immunodeficiency virus-infected rhesus macaques.mucosa-associated invariant t (mait) cells contribute to host immune protection against a wide range of potential pathogens via the recognition of bacterial metabolites presented by the major histocompatibility complex class i-related molecule mr1. although bacterial products translocate systemically in human immunodeficiency virus (hiv)-infected individuals and simian immunodeficiency virus (siv)-infected asian macaques, several studies have shown that mait cell frequencies actually decrease in ...201626912615
lymphatic dissemination of simian immunodeficiency virus after penile inoculation.the human immunodeficiency virus (hiv) is primarily transmitted by heterosexual contact, and approximately equal numbers of men and women worldwide are infected with the virus. understanding the biology of hiv acquisition and dissemination in men exposed to the virus by insertive penile intercourse is likely to help with the rational design of vaccines that can limit or prevent hiv transmission. to characterize the target cells and dissemination pathways involved in establishing systemic simian ...201626865706
prevention of shiv transmission by topical ifn-β treatment.understanding vaginal and rectal hiv transmission and protective cellular and molecular mechanisms is critical for designing new prevention strategies, including those required for an effective vaccine. the determinants of protection against hiv infection are, however, poorly understood. increasing evidence suggest that innate immune defenses may help protect mucosal surfaces from hiv transmission in highly exposed, uninfected subjects. more recent studies suggest that systemically administered ...201626838048
broadly targeted cd8⁺ t cell responses restricted by major histocompatibility complex e.major histocompatibility complex e (mhc-e) is a highly conserved, ubiquitously expressed, nonclassical mhc class ib molecule with limited polymorphism that is primarily involved in the regulation of natural killer (nk) cells. we found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes rh157.5 and rh157.4 are deleted results in mhc-e-restricted presentation of highly varied peptide epitopes to cd8αβ(+) t cells, at ~4 distinct epitopes per 100 amino acids in all te ...201626797147
assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.an established macaque model to assess hiv interventions against penile transmission is currently not available. physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (pk). here, we identify methods to establish erections in macaques to evaluate penile transmission, pk, and efficacy under physiologic conditions.201626778321
the presence of protective cytotoxic t lymphocytes does not correlate with shorter lifespans of productively infected cells in hiv-1 infection.cd8+ cytotoxic t lymphocytes (ctl) are important in the control of hiv infection. although ctl are thought to reduce the lifespan of productively infected cells, cd8+ t-cell depletion in simian immunodeficiency virus-infected rhesus-macaques showed no effect on the lifespan of productively infected cells. as cd8+ t-cell responses that successfully delay hiv disease progression occur only in a minority of hiv-infected individuals, we studied the hypothesis that the ability of ctl to reduce the li ...201626731751
translocation of microbes and changes of immunocytes in the gut of rapid- and slow-progressor chinese rhesus macaques infected with sivmac239.human/simian immunodeficiency virus (hiv/siv) infection can cause severe depletion of cd4(+) t cells in both plasma and mucosa; it also results in damage to the gut mucosa barrier, which makes the condition more conducive to microbial translocation. in this study, we used siv-infected chinese rhesus macaques to quantify the extent of microbial translocation and the function of immune cells in the entire gastrointestinal tract and to compare their differences between rapid and slow progressors. t ...201626725773
host anti-antibody responses following adeno-associated virus-mediated delivery of antibodies against hiv and siv in rhesus monkeys.long-term delivery of antibodies against the human immunodeficiency virus (hiv) using adeno-associated virus (aav) vectors is a promising approach for the prevention or treatment of hiv infection. however, host antibody responses to the delivered antibody are a serious concern that could significantly limit the applicability of this approach. here, we describe the dynamics and characteristics of the anti-antibody responses in monkeys that received either rhesus anti-simian immunodeficiency virus ...201626444083
longitudinal assessment of fractional anisotropy alterations caused by simian immunodeficiency virus infection: a preliminary diffusion tensor imaging study.previous diffusion tensor imaging (dti) studies found that human immunodeficiency virus (hiv) infection led to white matter (wm) microstructure degeneration. most of the dti studies were cross-sectional and thus merely investigated only one specific point in the disease. in order to systematically study the wm impairments caused by hiv infection, more longitudinal studies are needed. however, longitudinal studies on hiv patients are very difficult to conduct. to address this question, we employe ...201626438160
siv/shiv infection triggers vascular inflammation, diminished expression of krüppel-like factor 2 and endothelial dysfunction.human immunodeficiency virus (hiv) infection is associated with increased risk of thromboembolic and cardiovascular comorbid conditions. although systemic inflammation is linked to cardiovascular risk, direct evidence of vascular inflammation and endothelial dysfunction is lacking.201626671887
gut immune dysfunction through impaired innate pattern recognition receptor expression and gut microbiota dysbiosis in chronic siv infection.hiv targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. however, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (prrs) during hiv infection and disease progression are not well defined. using the simian immunodeficiency virus (siv)-infected rhesus macaque model of aids, we found a robust increase in prrs and inflammatory cytokine gene expression during the acute siv infection in both ...201626376368
chronic binge alcohol administration dysregulates hippocampal genes involved in immunity and neurogenesis in simian immunodeficiency virus-infected macaques.alcohol use disorders (aud) exacerbate neurocognitive dysfunction in human immunodeficiency virus (hiv+) patients. we have shown that chronic binge alcohol (cba) administration (13-14 g etoh/kg/wk) prior to and during simian immunodeficiency virus (siv) infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. the underlying mechanisms of neurocognitive alterations due to alcohol and siv are not known. this exploratory study examined the cba-induced differentia ...201627834864
mucosal and systemic γδ+ t cells associated with control of simian immunodeficiency virus infection.γδ t cells act as a first line of defense against invading pathogens. however, despite their abundance in mucosal tissue, little information is available about their functionality in this compartment in the context of hiv/siv infection. in this study, we evaluated the frequency, phenotype, and functionality of vδ1 and vδ2 t cells from blood, rectum, and the female reproductive tract (frt) of rhesus macaques to determine whether these cells contribute to control of siv infection. no alteration in ...201627815422
il-21-producer cd4+ t cell kinetics during primary simian immunodeficiency virus infection.il-21 signaling is important for t cell and b cell-mediated clearance of chronic viral infections. while non-cognate follicular helper cd4+ t cells (tfh) are indicated to be pivotal in providing il-21-mediated help to activated b cells within germinal centers, how this signaling may be disrupted in early aids virus infection is not clear. in this study, we assessed the lineage and kinetics of peripheral blood il-21-producing cd4+ t cells in primary simian immunodeficiency virus (siv) infection o ...201623791954
high doses of gm-csf inhibit antibody responses in rectal secretions and diminish modified vaccinia ankara/simian immunodeficiency virus vaccine protection in trim5α-restrictive macaques.we tested, in rhesus macaques, the effects of a 500-fold range of an admixed recombinant modified vaccinia ankara (mva) expressing rhesus gm-csf (mva/gm-csf) on the immunogenicity and protection elicited by an mva/siv macaque 239 vaccine. high doses of mva/gm-csf did not affect the levels of systemic envelope (env)-specific ab, but it did decrease the expression of the gut-homing receptor α4β7 on plasmacytoid dendritic cells (p < 0.01) and the magnitudes of env-specific iga (p = 0.01) and igg (p ...201627683750
short communication: comparative evaluation of coformulated injectable combination antiretroviral therapy regimens in simian immunodeficiency virus-infected rhesus macaques.the use of nonhuman primate (nhp) models to study persistent residual virus and viral eradication strategies in combination antiretroviral therapy (cart)-treated individuals requires regimens that effectively suppress siv replication to clinically relevant levels in macaques. we developed and evaluated two novel cart regimens in sivmac239-infected rhesus macaques: (1) a "triple regimen" containing the nucleo(s/t)ide reverse transcriptase inhibitors emtricitabine (ftc) and tenofovir disoproxil fu ...201626150024
siv infection-mediated changes in gastrointestinal bacterial microbiome and virome are associated with immunodeficiency and prevented by vaccination.aids caused by simian immunodeficiency virus (siv) infection is associated with gastrointestinal disease, systemic immune activation, and, in cross-sectional studies, changes in the enteric virome. here we performed a longitudinal study of a vaccine cohort to define the natural history of changes in the fecal metagenome in siv-infected monkeys. matched rhesus macaques were either uninfected or intrarectally challenged with siv, with a subset receiving the ad26 vaccine, an adenovirus vector expre ...201626962943
evaluation of functional nk cell responses in vaccinated and siv-infected rhesus macaques.nk cells are crucial components of the innate immune system due to their capacity to exert rapid cytotoxic and immunomodulatory function in the absence of prior sensitization. nk cells can become activated by exposure to target cells and/or by cytokines produced by antigen-presenting cells. in this study, we examined the effects of a simian immunodeficiency virus (siv) vaccine regimen and subsequent siv infection on the cytotoxic and immunomodulatory functions of circulatory nk cells. while vacc ...201627630641
correction for rife et al., evolution of neuroadaptation in the periphery and purifying selection in the brain contribute to compartmentalization of simian immunodeficiency virus (siv) in the brains of rhesus macaques with siv-associated encephalitis. 201627620914
[effect of chinese herbal extract hna-1 on the thymic output function in simian immunodeficiency virus chronically infected chinese rhesus macaques].to observe the effect of chinese herbal extract hunan a-1 (hna-1) on the thymic output function in simian immunodeficiency virus (siv) chronically infected rhesus macaques.201627236896
δ9-tetrahydrocannabinol (δ9-thc) promotes neuroimmune-modulatory microrna profile in striatum of simian immunodeficiency virus (siv)-infected macaques.cannabinoid administration before and after simian immunodeficiency virus (siv)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. δ9-tetrahydrocannabinol (δ9-thc) did not increase viral load in brain tissue or produce additive neuropsychological impairment in siv-infected macaques. to determine if the neuroimmunomodulation of δ9-thc involved differential microrna (mir) expression, mir expression in the striatum of uninfected macaques receiving vehicl ...201626607731
increases in nkg2c expression on t cells and higher levels of circulating cd8(+) b cells are associated with sterilizing immunity provided by a live attenuated siv vaccine.vaccines based on live attenuated viruses are highly effective immunogens in the simian immunodeficiency virus (siv)/rhesus macaque animal model and offer the possibility of studying correlates of protection against infection with virulent virus. we utilized a tether system for studying, in naive macaques and animals vaccinated with a live-attenuated vaccine, the acute events after challenge with pathogenic siv. this approach allowed for the frequent sampling of small blood volumes without sedat ...201726986800
a method for obtaining simian immunodeficiency virus rna sequences from laser capture microdissected and immune captured cd68+ and cd163+ macrophages from frozen tissue sections of bone marrow and brain.laser capture microdissection (lcm) is used to extract cells or tissue regions for analysis of rna, dna or protein. several methods of lcm are established for different applications, but a protocol for consistently obtaining lentiviral rna from lcm captured immune cell populations is not described. obtaining optimal viral rna for analysis of viral genes from immune-captured cells using immunohistochemistry (ihc) and lcm is challenging. ihc protocols have long antibody incubation times that incre ...201728093272
altered regional homogeneity of brain spontaneous signals in siv infected rhesus macaque model.regional homogeneity (reho), a measurement from resting-state functional magnetic imaging (rs-fmri) to reflect local synchronization of brain activities, has been widely explored in previous studies of neurological diseases. siv infected model for detecting the neurological changes with progression was studied.201727989909
cabotegravir long acting injection protects macaques against intravenous challenge with sivmac251.we evaluated the effectiveness of cabotegravir (cab; gsk1265744 or gsk744) long acting as preexposure prophylaxis (prep) against intravenous simian immunodeficiency virus (siv) challenge in a model that mimics blood transfusions based on the per-act probability of infection.201727902508
the chitinases expression is related to simian immunodeficiency virus encephalitis (sive) and in hiv encephalitis (hive).human immunodeficiency virus (hiv) infection can induce neurocognitive complications classified as hiv-associated neurocognitive disorder (hand). the chitinase family is associated with innate immunity cells and many infectious diseases.201727794455
epithelium-innate immune cell axis in mucosal responses to siv.in the siv (simian immunodeficiency virus)-rhesus macaque model of hiv-1 (human immunodeficiency virus type i) transmission to women, one hallmark of the mucosal response to exposure to high doses of siv is cd4 t-cell recruitment that fuels local virus expansion in early infection. in this study, we systematically analyzed the cellular events and chemoattractant profiles in cervical tissues that precede cd4 t-cell recruitment. we show that vaginal exposure to the siv inoculum rapidly induces che ...201727435105
balancing trained immunity with persistent immune activation and the risk of simian immunodeficiency virus infection in infant macaques vaccinated with attenuated mycobacterium tuberculosis or mycobacterium bovis bcg vaccine.our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (hiv-1) and tuberculosis (tb) infections. the vaccine consists of an auxotroph mycobacterium tuberculosis strain that coexpresses hiv antigens. utilizing an infant rhesus macaque model, we have previously shown that this attenuated m. tuberculosis (amtb)-simian immunodeficiency virus (siv) vaccine is immunogenic, and although the vaccine did not prevent o ...201727655885
administration of an activin receptor iib ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss.hiv-infected individuals are at an increased risk of osteoporosis despite effective viral suppression. observations that myostatin null mice have increased bone mass led us to hypothesize that simian immunodeficiency virus (siv)-associated bone loss may be attenuated by blocking myostatin/tgfβ signaling. in this proof-of-concept study, pair-housed juvenile male rhesus macaques were inoculated with sivmac239. four weeks later, animals were treated with vehicle or fc-conjugated soluble activin rec ...201728132908
functional effector memory t cells contribute to protection from superinfection with heterologous simian immunodeficiency virus or simian-human immunodeficiency virus isolates in chinese rhesus macaques.many studies have revealed a protective effect of infection of an individual with an immunodeficiency virus against subsequent infection with a heterologous strain. however, the extent of protection against superinfection conferred by the first infection and the biological consequences of superinfection are not well understood. here, we report that a rhesus monkey model of mucosal superinfection was established to investigate the protective immune response. protection against superinfection was ...201728110425
controlling multicycle replication of live-attenuated hiv-1 using an unnatural genetic switch.a safe and effective human immunodeficiency virus type 1 (hiv-1) vaccine is urgently needed, but remains elusive. while hiv-1 live-attenuated vaccine can provide potent protection as demonstrated in rhesus macaque-simian immunodeficiency virus model, the potential pathogenic consequences associated with the uncontrolled virus replication preclude such vaccine from clinical applications. we investigated a novel approach to address this problem by controlling live-attenuated hiv-1 replication thro ...201728106981
dynamic modulation of expression of lentiviral restriction factors in primary cd4(+) t cells following simian immunodeficiency virus infection.although multiple restriction factors have been shown to inhibit hiv/siv replication, little is known about their expression in vivo expression of 45 confirmed and putative hiv/siv restriction factors was analyzed in cd4(+) t cells from peripheral blood and the jejunum in rhesus macaques, revealing distinct expression patterns in naive and memory subsets. in both peripheral blood and the jejunum, memory cd4(+) t cells expressed higher levels of multiple restriction factors compared to naive cell ...201728100613
changes in circulating b cell subsets associated with aging and acute siv infection in rhesus macaques.aging and certain viral infections can negatively impact humoral responses in humans. to further develop the nonhuman primate (nhp) model for investigating b cell dynamics in human aging and infectious disease, a flow cytometric panel was developed to characterize circulating rhesus b cell subsets. significant differences between human and macaque b cells included the proportions of cells within igd+ and switched memory populations and a prominent cd21-cd27+ unswitched memory population detected ...201728095513
chronic binge alcohol-induced dysregulation of mitochondrial-related genes in skeletal muscle of simian immunodeficiency virus-infected rhesus macaques at end-stage disease.alcohol use disorders are more prevalent in hiv patients than the general population. both chronic alcohol consumption and hiv infection have been linked to mitochondrial dysregulation; and this is considered an important mechanism in the pathogenesis of muscle myopathy. this study investigated if chronic binge alcohol (cba) administration impairs the expression of genes involved in mitochondrial homeostasis in siv-infected macaques.201728069597
kinetics of myeloid-derived suppressor cell frequency and function during simian immunodeficiency virus infection, combination antiretroviral therapy, and treatment interruption.during chronic lentiviral infection, poor clinical outcomes correlate both with systemic inflammation and poor proliferative ability of hiv-specific t cells; however, the connection between the two is not clear. myeloid-derived suppressor cells (mdsc), which expand during states of elevated circulating inflammatory cytokines, may link the systemic inflammation and poor t cell function characteristic of lentiviral infections. although mdsc are partially characterized in hiv and siv infection, que ...201727974456
influence of plasma cell niche factors on the recruitment and maintenance of irf4hi plasma cells and plasmablasts in vaccinated, simian immunodeficiency virus-infected rhesus macaques with low and high viremia.in a recent study, we found that protection following simian immunodeficiency virus (siv) exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. we sought to determine if the same macaques maintained high mucosal plasma cell frequencies postinfection and if this translated to reduced viremia. although delayed siv acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that ...201727928009
adjuvanting a simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in trim5α restrictive macaques.our previous work has shown that antigens adjuvanted with ligands specific for toll-like receptor 4 (tlr4) and tlr7/8 encapsulated in poly(lactic-co-glycolic) acid (plga)-based nanoparticles (nps) induce robust and durable immune responses in mice and macaques. we investigated the efficacy of these np adjuvants in inducing protective immunity against simian immunodeficiency virus (siv). rhesus macaques (rms) were immunized with nps containing tlr4 and tlr7/8 agonists mixed with soluble recombina ...201727928002
soluble tlr2 and 4 concentrations in cerebrospinal fluid in hiv/siv-related neuropathological conditions.hiv in the central nervous system (cns) mainly infects microglial cells which are known to express toll-like receptors (tlrs). this paper aimed to study the role of soluble tlr2 (stlr2), stlr4, and other inflammatory markers in cerebrospinal fluid (csf) in hiv/simian immunodeficiency virus (siv)-related neurological sequelae. we determined stlr2 and stlr4 levels in csf and serum/plasma of siv-infected rhesus macaques with and without neurological sequelae, as well as in hiv-infected patients wit ...201727882497
mzc gel inhibits shiv-rt and hsv-2 in macaque vaginal mucosa and shiv-rt in rectal mucosa.the population council's microbicide gel mzc (also known as pc-1005) containing miv-150 and zinc acetate dihydrate (za) in carrageenan (cg) has shown promise as a broad-spectrum microbicide against hiv, herpes simplex virus (hsv), and human papillomavirus. previous data show antiviral activity against these viruses in cell-based assays, prevention of vaginal and rectal simian-human immunodeficiency virus reverse transcriptase (shiv-rt) infection, and reduction of vaginal hsv shedding in rhesus m ...201727552154
plasmablast response to primary rhesus cytomegalovirus infection in a monkey model of congenital cmv transmission.human cytomegalovirus (hcmv) is the most common congenital infection worldwide, and the leading infectious cause of neurologic deficits and hearing loss in newborns. development of a maternal hcmv vaccine to prevent vertical virus transmission is a high priority, yet protective maternal immune responses following acute infection are poorly understood. to characterize the maternal humoral immune response to primary cmv infection, we investigated the plasmablast and early antibody repertoire using ...201728298291
evaluation of vaginal drug levels and safety of a locally administered glycerol monolaurate cream in rhesus macaques.the human immunodeficiency virus (hiv) epidemic affects millions of people worldwide. as women are more vulnerable to infection, female-controlled interventions can help control the spread of the disease significantly. glycerol monolaurate (gml), an inexpensive and safe compound, has been shown to protect against simian immunodeficiency virus infection when applied vaginally. however, due to its low aqueous solubility, fabrication of high dose formulations of gml has proven difficult. we describ ...201728389267
what is the predictive value of animal models for vaccine efficacy in humans? rigorous simian immunodeficiency virus vaccine trials can be instructive.simian immunodeficiency virus (siv) challenge of rhesus macaques provides an invaluable tool to evaluate the clinical prospects of hiv-1 vaccine concepts. however, as with any animal model of human disease, it is crucial to understand the advantages and limitations of this system to maximize the translational value of siv vaccine studies. here, we discuss the importance of assessing the efficacy of vaccine prototypes using stringent siv challenge regimens that mimic hiv-1 transmission and pathog ...201728348034
hiv-1 tat primes and activates microglial nlrp3 inflammasome-mediated neuroinflammation.neuroinflammation associated with hiv-1 infection is a problem affecting ∼50% of hiv-infected individuals. nlr family pyrin domain containing 3 (nlrp3) inflammasome has been implicated in hiv-induced microglial activation, but the mechanism(s) remain unclear. because hiv-1 transactivator of transcription (tat) protein continues to be present despite antiretroviral therapy and activates nf-kb, we hypothesized that tat could prime the nlrp3 inflammasome. we found a dose- and time-dependent inducti ...201728270571
rhesus macaque ifitm3 gene polymorphisms and siv infection.interferon-induced transmembrane proteins (ifitms) have been recognized as important antiviral effectors of the innate immune system, both in cell culture and in infected humans. in particular, polymorphisms of the human ifitm3 gene have been shown to affect disease severity and progression in influenza a virus (fluav) and human immunodeficiency virus (hiv) infection, respectively. rhesus macaques (macaca mulatta) are commonly used to model human infections and the experimental inoculation of th ...201728257482
accelerated disease progression and robust innate host response in aged sivmac239-infected chinese rhesus macaques is associated with enhanced immunosenescence.the elderly population infected with hiv-1 is often characterized by the rapid aids progression and poor treatment outcome, possibly because of immunosenescence resulting from both hiv infection and aging. however, this hypothesis remains to be fully tested. here, we studied 6 young and 12 old chinese rhesus macaques (chrm) over the course of three months after simian immunodeficiency virus (siv) sivmac239 infection. old chrm showed a higher risk of accelerated aids development than did young ma ...201728232735
vpx overcomes a samhd1-independent block to hiv reverse transcription that is specific to resting cd4 t cells.early after entry into monocytes, macrophages, dendritic cells, and resting cd4 t cells, hiv encounters a block, limiting reverse transcription (rt) of the incoming viral rna genome. in this context, dntp triphosphohydrolase sam domain and hd domain-containing protein 1 (samhd1) has been identified as a restriction factor, lowering the concentration of dntp substrates to limit rt. the accessory lentiviral protein x (vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, so ...201728228523
menin mediates tat-induced neuronal apoptosis in brain frontal cortex of siv-infected macaques and in tat-treated cells.the molecular mechanisms involved in human immunodeficiency virus (hiv)-associated neurocognitive disorder (hand) remain poorly understood. it has been recently reported that hiv-1 tat transactivation requires menin, suggesting that menin may be involved in hand pathogenesis. but the role of menin is not clear. here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (shiv)-sf162.p4 and simian immunodeficiency virus (siv) sm543-3-infected rhesus ma ...201728178646
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