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liver-directed but not muscle-directed aav-antibody gene transfer limits humoral immune responses in rhesus monkeys.a number of publications have described the use of adeno-associated virus (aav) for the delivery of anti-hiv and anti-simian immunodeficiency virus (siv) monoclonal antibodies (mabs) to rhesus monkeys. anti-drug antibodies (adas) have been frequently observed, and long-term aav-mediated delivery has been inconsistent. here, we investigated different aav vector strategies and delivery schemes to rhesus monkeys using the rhesus monkey mab 4l6. we compared 4l6 immunoglobulin g1 (igg1) delivery usin ...202031890736
genetically barcoded siv reveals the emergence of escape mutations in multiple viral lineages during immune escape.the rapidity of replication coupled with a high mutation rate enables hiv to evade selective pressures imposed by host immune responses. investigating the ability of hiv to escape different selection forces has generally relied on population-level measures, such as the time to detectable escape mutations in plasma and the rate these mutations subsequently take over the virus population. here we employed a barcoded synthetic swarm of simian immunodeficiency virus (siv) in rhesus macaques to inves ...202031843933
perivascular macrophages in the neonatal macaque brain undergo massive necroptosis after simian immunodeficiency virus infection.we previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (siv) do not develop siv encephalitis (sive) and maintain low brain viral loads despite having similar plasma viral loads compared to siv-infected adults. we hypothesize that differences in myeloid cell populations that are the known target of siv and hiv in the brain contribute to the lack of neonatal susceptibility to lentivirus-induced encephalitis. using immunohistochemistry and immunofluorescenc ...202031834964
a muc16 igg binding activity selects for a restricted subset of igg enriched for certain simian immunodeficiency virus epitope specificities.we have recently shown that muc16, a component of the glycocalyx of some mucosal barriers, has elevated binding to the g0 glycoform of the fc portion of igg. therefore, igg from patients chronically infected with human immunodeficiency virus (hiv), who typically exhibit increased amounts of g0 glycoforms, showed increased muc16 binding compared to uninfected controls. using the rhesus macaque simian immunodeficiency virus sivmac251 model, we can compare plasma antibodies before and after chronic ...202031776284
transient immune activation in bcg-vaccinated infant rhesus macaques is not sufficient to influence oral simian immunodeficiency virus infection.bcg vaccination has been demonstrated to increase levels of activated cd4+ t cells, thus potentially influencing mother-to-child transmission of human immunodeficiency virus (hiv). to assess the risk of bcg vaccination in hiv infection, we randomly assigned newborn rhesus macaques to receive bcg vaccine or remain unvaccinated and then undergo oral simian immunodeficiency virus (siv) challenges 3 weeks later. we observed elevated levels of activated peripheral cd4+ t cells (ie, hla-dr+cd38+ccr5+ ...202031605528
recombinant human interleukin-15 and anti-pd-l1 combination therapy expands a cxcr3+pd1-/low cd8 t-cell subset in simian immunodeficiency virus-infected rhesus macaques.the pd1/pd-l1 pathway contributes to the pathogenesis of human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) infection, and blockade of this pathway may have potential to restore immune function and promote viral control or elimination. in this study, we combined a checkpoint inhibitor anti-pd-l1 (avelumab) and recombinant human interleukin-15 (rhil-15) in siv-infected rhesus macaques (rm).202031562760
siv-mediated synaptic dysfunction is associated with an increase in synapsin site 1 phosphorylation and impaired pp2a activity.although the reduction of viral loads in people with hiv undergoing combination antiretroviral therapy has mitigated aids-related symptoms, the prevalence of neurological impairments has remained unchanged. hiv-associated cns dysfunction includes impairments in memory, attention, memory processing, and retrieval. here, we show a significant site-specific increase in the phosphorylation of syn i serine 9, site 1, in the frontal cortex lysates and synaptosome preparations of male rhesus macaques i ...201931270156
gut microbiome alterations during hiv/siv infection: implications for hiv cure.gut mucosal damage, associated with human immunodeficiency virus-1 (hiv) infection, is characterized by depletion in cd4+ t cells and persistent immune activation as a result of early epithelial barrier disruption and systemic translocation of microbial products. unique approaches in studying both hiv infection in human patients and simian immunodeficiency virus (siv) infection in rhesus macaques have provided critical evidence for the pathogenesis and treatment of hiv/aids. while there is vast ...201931191468
comparative analysis of gammaherpesvirus circular rna repertoires: conserved and unique viral circular rnas.recent studies have identified circular rnas (circrnas) expressed from the epstein-barr virus (ebv) and kaposi's sarcoma herpesvirus (kshv) human dna tumor viruses. to gain initial insights into the potential relevance of ebv circrnas in virus biology and disease, we assessed the circrnaome of the interspecies homologue rhesus macaque lymphocryptovirus (rlcv) in a naturally occurring lymphoma from a simian immunodeficiency virus (siv)-infected rhesus macaque. this analysis revealed rlcv ortholog ...201930567979
cannabinoid attenuation of intestinal inflammation in chronic siv-infected rhesus macaques involves t cell modulation and differential expression of micro-rnas and pro-inflammatory genes.cannabis use is frequent in hiv-infected individuals for its appetite stimulation and anti-inflammatory effects. to identify the underlying molecular mechanisms associated with these effects, we simultaneously profiled micro-rna (mirna) and mrna expression in the colon of chronically simian immunodeficiency virus (siv)-infected rhesus macaques administered either vehicle (veh/siv; n = 9) or δ9-tetrahydrocannabinol (δ9-thc; thc/siv; n = 8). pro-inflammatory mir-130a, mir-222, and mir-29b, lipopol ...201931114576
shifting dynamics of intestinal macrophages during simian immunodeficiency virus infection in adult rhesus macaques.the intestinal tract is a primary barrier to invading pathogens and contains immune cells, including lymphocytes and macrophages. we previously reported that cd163+cd206- (single-positive [sp]) interstitial macrophages of the lung are short-lived and succumb early to siv infection. conversely, cd163+cd206+ (double-positive [dp]) alveolar macrophages are long-lived, survive after siv infection, and may contribute to the virus reservoir. this report characterizes analogous populations of macrophag ...201930926643
cd8+ t cell-based strong selective pressure on multiple simian immunodeficiency virus targets in macaques possessing a protective mhc class i haplotype.in human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) infections, host major histocompatibility complex class i (mhc-i) genotypes have a great impact on viral replication and mhc-i-associated viral genome mutations are selected under cd8+ t-cell pressure. association of mhc-i genotypes with hiv/siv control has been investigated at mhc-i allele levels but not fully at haplotype levels. we previously established groups of rhesus macaques sharing individual mhc-i haplotypes. ...201930878187
design and characterization of cholesterylated peptide hiv-1/2 fusion inhibitors with extremely potent and long-lasting antiviral activity.hiv infection requires lifelong treatment with multiple antiretroviral drugs in a combination, which ultimately causes cumulative toxicities and drug resistance, thus necessitating the development of novel antiviral agents. we recently found that enfuvirtide (t-20)-based lipopeptides conjugated with fatty acids have dramatically increased in vitro and in vivo anti-hiv activities. herein, a group of cholesterol-modified fusion inhibitors were characterized with significant findings. first, novel ...201930867304
the new orleans alcohol use in hiv study: launching a translational investigation of the interaction of alcohol use with biological and socioenvironmental risk factors for multimorbidity in people living with hiv.alcohol use disorders (auds) are highly prevalent in people living with hiv (plwh) and are associated with increased hiv risk behaviors, suboptimal treatment adherence, potential interaction with medication pharmacodynamics, and greater risk for disease progression. preclinical studies show that chronic binge alcohol administration accelerates disease progression and aggravates pathogenesis in the simian immunodeficiency virus (siv)-infected rhesus macaque model despite viral suppression by anti ...201930748025
a live-attenuated rhcmv/siv vaccine shows long-term efficacy against heterologous siv challenge.previous studies have established that strain 68-1-derived rhesus cytomegalovirus (rhcmv) vectors expressing simian immunodeficiency virus (siv) proteins (rhcmv/siv) are able to elicit and maintain cellular immune responses that provide protection against mucosal challenge of highly pathogenic siv in rhesus monkeys (rms). however, these efficacious rhcmv/siv vectors were replication and spread competent and therefore have the potential to cause disease in immunocompromised subjects. to develop a ...201931316007
hla-e: exploiting pathogen-host interactions for vaccine development.viruses, when used as vectors for vaccine antigen delivery, can induce strong cellular and humoral responses against target epitopes. recent work by hansen et al. describes the use of a cytomegalovirus-vectored vaccine, which is able to generate a stable effector-memory t cell population at the sites of vaccination in rhesus macaques. this vaccine, targeted towards multiple epitopes in simian immunodeficiency virus (siv), did not induce classical cd8+ t cells. however, non-canonical cd8+ t cell ...201930968409
differential effect of mucosal nkp44+ innate lymphoid cells and δγ cells on simian immunodeficiency virus infection outcome in rhesus macaques.nk cells are essential for controlling viral infections. we investigated nk cell and innate lymphoid cell (ilc) dynamics and function in rhesus macaque rectal tissue and blood following mucosal priming with replicating adenovirus (ad)-siv recombinants, systemic boosting with siv envelope protein, and subsequent repeated low-dose intravaginal siv exposures. mucosal memory-like nk and ilc subsets in rectal and vaginal tissues of chronically infected macaques were also evaluated. no differences in ...201931554692
evaluating the intactness of persistent viral genomes in simian immunodeficiency virus-infected rhesus macaques after initiating antiretroviral therapy within one year of infection.the major obstacle to more-definitive treatment for hiv infection is the early establishment of virus that persists despite long-term combination antiretroviral therapy (cart) and can cause recrudescent viremia if cart is interrupted. previous studies of hiv dna that persists despite cart indicated that only a small fraction of persistent viral sequences was intact. experimental simian immunodeficiency virus (siv) infections of nonhuman primates (nhps) are essential models for testing interventi ...201931597776
in vivo validation of the viral barcoding of simian immunodeficiency virus sivmac239 and the development of new barcoded siv and subtype b and c simian-human immunodeficiency viruses.genetically barcoded viral populations are powerful tools for evaluating the overall viral population structure as well as assessing the dynamics and evolution of individual lineages in vivo over time. barcoded viruses are generated by inserting a small, genetically unique tag into the viral genome, which is retained in progeny virus. we recently reported barcoding the well-characterized molecular clone simian immunodeficiency virus (siv) sivmac239, resulting in a synthetic swarm (sivmac239m) co ...201931597757
vaccine protection against rectal acquisition of sivmac239 in rhesus macaques.a prophylactic vaccine against human immunodeficiency virus (hiv) remains a top priority in biomedical research. given the failure of conventional immunization protocols to confer robust protection against hiv, new and unconventional approaches may be needed to generate protective anti-hiv immunity. here we vaccinated rhesus macaques (rms) with a recombinant (r)dna prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (rrv)-a herpesvirus that establishes p ...201931568531
lack of therapeutic efficacy of an antibody to α4β7 in sivmac251-infected rhesus macaques.sustained virologic control of human immunodeficiency virus type 1 (hiv-1) infection after discontinuation of antiretroviral therapy (art) is a major goal of the hiv-1 cure field. a recent study reported that administration of an antibody against α4β7 induced durable virologic control after art discontinuation in 100% of rhesus macaques infected with an attenuated strain of simian immunodeficiency virus (siv) containing a stop codon in nef we performed similar studies in 50 rhesus macaques infec ...201931488689
role of il-15 signaling in the pathogenesis of simian immunodeficiency virus infection in rhesus macaques.although il-15 has been implicated in the pathogenic hyperimmune activation that drives progressive hiv and siv infection, as well as in the generation of hiv/siv target cells, it also supports nk and t cell homeostasis and effector activity, potentially benefiting the host. to understand the role of il-15 in siv infection and pathogenesis, we treated two cohorts of sivmac239-infected rhesus macaques (rm; macaca mulatta), one with chronic infection, the other with primary infection, with a rhesu ...201931653683
engineering of a lectibody targeting high-mannose-type glycans of the hiv envelope.high-mannose-type glycans (hmgs) are aberrantly enriched on hiv envelope glycoproteins. however, there is currently no drug selectively targeting hiv-associated hmgs. here, we describe a novel hmg-targeting "lectibody," a recombinant fc-fusion protein comprising human igg1 fc and a novel actinohivin lectin variant (avaren) obtained by structure-guided modifications for improved overall surface charge properties (avfc). avfc was engineered and produced using a rapid and scalable plant-based trans ...201931471224
preferential small intestine homing and persistence of cd8 t cells in rhesus macaques achieved by molecularly engineered expression of ccr9 and reduced ex vivo manipulation.adoptive cell transfer (act) is a powerful experimental approach to directly study t-cell-mediated immunity in vivo in the rhesus macaque aids virus model, infusing simian immunodeficiency virus (siv)-infected animals with cd8 t cells engineered to express anti-siv t-cell receptor specificities enables direct experimentation to better understand antiviral t-cell immunity in vivo limiting factors in act experiments include suboptimal trafficking to, and poor persistence in, the secondary lymphoid ...201931434738
epigenomic mechanisms of alcohol-induced impaired differentiation of skeletal muscle stem cells; role of class iia histone deacetylases.loss of functional metabolic muscle mass remains a strong and consistent predictor of mortality among people living with human immunodeficiency virus (plwh). plwh have a higher incidence of alcohol use disorder (aud), and myopathy is a significant clinical comorbidity due to aud. one mechanism of skeletal muscle (skm) mass maintenance and repair is by differentiation and fusion of satellite cells (scs) to existing myofibers. previous studies demonstrated that chronic binge alcohol (cba) administ ...201931398085
chronic binge alcohol-associated differential brain region modulation of growth factor signaling pathways and neuroinflammation in simian immunodeficiency virus-infected male macaques.microarray analysis of hippocampal tissue from chronic binge alcohol (cba)-administered, simian immunodeficiency virus (siv)-infected male macaques identified altered immune response and neurogenesis as potential mechanisms underlying cognitive deficits in macaques. this study investigated the differential brain region associations between markers of neuroinflammation and growth factor signaling with microtubule-associated protein 2 (map2) expression.201931322648
intestinal proteomic analysis of a novel non-human primate model of experimental colitis reveals signatures of mitochondrial and metabolic dysfunction.animal models recapitulating features of chronic colitis, such as ulcerative colitis, crohn's disease, or hiv infection, are critical to study disease pathogenesis and test novel therapeutics. in this study, we used a proteomics approach to explore the molecular intestinal response in two rhesus macaque (rm) animal models of experimentally induced colitis using dextran sulfate sodium (dss) and simian immunodeficiency virus (siv) infection. proteomic analysis detected more than 2500 proteins in c ...201931481749
enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity.rhesus cytomegalovirus (rhcmv)-based vaccines maintain effector memory t cell responses (tem) that protect ~50% of rhesus monkeys (rms) challenged with simian immunodeficiency virus (siv). because human cmv (hcmv) causes disease in immunodeficient subjects, clinical translation will depend upon attenuation strategies that reduce pathogenic potential without sacrificing cmv's unique immunological properties. we demonstrate that "intrinsic" immunity can be used to attenuate strain 68-1 rhcmv vecto ...201931316006
differential dynamics of regulatory t-cell and th17 cell balance in mesenteric lymph nodes and blood following early antiretroviral initiation during acute simian immunodeficiency virus infection.increased frequencies of immunosuppressive regulatory t cells (tregs) are associated with gut lymphoid tissue fibrosis and dysfunction which, in turn, contribute to disease progression in chronic simian immunodeficiency virus/human immunodeficiency virus (siv/hiv) infection. mesenteric lymph nodes (mlns), which drain the large and small intestine, are critical sites for the induction and maintenance of gut mucosal immunity. however, the dynamics of tregs in mlns are not well understood due to th ...201931315987
persistent viral reservoirs in lymphoid tissues in siv-infected rhesus macaques of chinese-origin on suppressive antiretroviral therapy.understanding hiv latent reservoirs in tissues is essential for the development of new strategies targeting these sites for eradication. here, we assessed the size of latent reservoirs and the source of residual viruses in multiple lymphoid tissues of siv-infected and fully suppressed rhesus macaques of chinese-origin (crms). eight crms were infected with sivmac251 and treated with tenofovir and emtricitabine daily for 24 weeks initiated 4 weeks post-infection. four of the eight animals reached ...201930691203
kynurenine 3-monooxygenase inhibition during acute simian immunodeficiency virus infection lowers pd-1 expression and improves post-combination antiretroviral therapy cd4+ t cell counts and body weight.the kynurenine pathway (kp) is a key regulator of many important physiological processes and plays a harmful role in cancer, many neurologic conditions, and chronic viral infections. in hiv infection, kp activity is consistently associated with reduced cd4 t cell counts and elevated levels of t cell activation and viral load; it also independently predicts mortality and morbidity from non-aids events. kynurenine 3-monooxygenase (kmo) is a therapeutically important target in the kp. using the non ...201931285277
antiretroviral therapy administration in healthy rhesus macaques is associated with transient shifts in intestinal bacterial diversity and modest immunological perturbations.gastrointestinal (gi) immune system competency is dependent upon interactions with commensal microbiota, which can be influenced by wide-ranging pharmacologic interventions. in simian immunodeficiency virus (siv)-infected asian macaque models of human immunodeficiency virus (hiv) infection, we previously noted that initiation of antiretroviral therapy (art) is associated with a specific imbalance (dysbiosis) of the composition of the intestinal bacteriome. to determine if art itself might contri ...201931270225
simian immunodeficiency virus transiently increases brain temperature in rhesus monkeys: detection with magnetic resonance spectroscopy thermometry.to evaluate brain temperature effects of early simian immunodeficiency virus (siv) infection in rhesus macaques using proton magnetic resonance spectroscopy (mrs) thermometry (mrst) and to determine whether temperature correlates with brain choline or myo-inositol levels.201930652349
simian immunodeficiency virus infection modulates cd94+ (klrd1+) nk cells in rhesus macaques.recently, we and others have shown that natural killer (nk) cells exhibit memory-like recall responses against cytomegalovirus (cmv) and human immunodeficiency/virus simian immunodeficiency virus (hiv/siv) infections. although the mechanism(s) have not been fully delineated, several groups have shown that the activating receptor nkg2c is elevated on nk cells in the context of rhesus cmv (rhcmv) or human cmv (hcmv) infections. cd94, which heterodimerizes with nkg2c is also linked to adaptive nk c ...201931167916
neuroinflammatory changes in relation to cerebrospinal fluid viral load in simian immunodeficiency virus encephalitis.the exact cause of neurocognitive dysfunction in hiv-positive patients despite successful control of the infection in the periphery is not completely understood. one suggested mechanism is a vicious cycle of microglial activation and release of proinflammatory chemokines/cytokines that eventually leads to neuronal loss and dysfunction. however, the exact role of microglial activation in the earliest stages of the infection with high cerebrospinal fluid (csf) viral loads (vl) is unclear. in this ...201931138753
correction for mavigner et al., "simian immunodeficiency virus persistence in cellular and anatomic reservoirs in antiretroviral therapy-suppressed infant rhesus macaques". 201930655382
lack of susceptibility in neonatally infected rhesus macaques to simian immunodeficiency virus-induced encephalitis.despite combination antiretroviral therapies making hiv a chronic rather than terminal condition for many people, the prevalence of hiv-associated neurocognitive disorders (hand) is increasing. this is especially problematic for children living with hiv. children diagnosed hand rarely display the hallmark pathology of hiv encephalitis in adults, namely infected macrophages and multinucleated giant cells in the brain. this finding has also been documented in rhesus macaques infected perinatally w ...201931119711
a pathogenic role for splenic b1 cells in siv disease progression in rhesus macaques.b1 cells spontaneously produce protective natural antibodies which provide the first line of defense against a variety of pathogens. although these natural antibodies share similar autoreactive features with several hiv-1 broadly neutralizing antibodies, the role of b1 cells in hiv/siv disease progression is unknown. we report the presence of human-like b1 cells in rhesus macaques. during chronic siv infection, we found that the frequency of splenic cd11b+ b1 cells positively correlated with pla ...201930941141
novel modified vaccinia virus ankara vector expressing anti-apoptotic gene b13r delays apoptosis and enhances humoral responses.modified vaccinia virus ankara (mva), an attenuated poxvirus, has been developed as a potential vaccine vector for use against cancer and multiple infectious diseases, including human immunodeficiency virus (hiv). mva is highly immunogenic and elicits strong cellular and humoral responses in preclinical models and humans. however, there is potential to further enhance the immunogenicity of mva, as mva-infected cells undergo rapid apoptosis, leading to faster clearance of recombinant antigens and ...201930541829
evolution of the gut microbiome following acute hiv-1 infection.in rhesus macaques, simian immunodeficiency virus infection is followed by expansion of enteric viruses but has a limited impact on the gut bacteriome. to understand the longitudinal effects of hiv-1 infection on the human gut microbiota, we prospectively followed 49 mozambican subjects diagnosed with recent hiv-1 infection (rhi) and 54 hiv-1-negative controls for 9-18 months and compared them with 98 chronically hiv-1-infected subjects treated with antiretrovirals (n = 27) or not (n = 71).201931078141
antibody fab-fc properties outperform titer in predictive models of siv vaccine-induced protection.characterizing the antigen-binding and innate immune-recruiting properties of the humoral response offers the chance to obtain deeper insights into mechanisms of protection than revealed by measuring only overall antibody titer. here, a high-throughput, multiplexed fab-fc array was employed to profile rhesus macaques vaccinated with a gp120-cd4 fusion protein in combination with different genetically encoded adjuvants, and subsequently subjected to multiple heterologous simian immunodeficiency v ...201931048360
chemokine receptor ccr5 correlates with functional cd8+ t cells in siv-infected macaques and the potential effects of maraviroc on t-cell activation.c-c chemokine receptor 5 (ccr5) plays an essential role in hiv pathogenesis as the major coreceptor on cd4+ t cells used by hiv, yet the function of ccr5 on cd8 t cells is not well understood. furthermore, the immunologic effects of the ccr5 inhibitor maraviroc (mvc), despite approval for clinical use, have not yet been well evaluated for their potential effects on cytotoxic t-cell responses. in this study, we characterized the development and function of ccr5+cd8+ t cells in rhesus macaques wit ...201931034775
replicating adenovirus-siv immunization of rhesus macaques induces mucosal dendritic cell activation and function leading to rectal immune responses.inducing strong mucosal immune responses by vaccination is important for providing protection against simian immunodeficiency virus (siv). a replicating adenovirus type 5 host range mutant vector (ad5hr) expressing siv proteins induced mucosal immune responses in rectal tissue associated with delayed siv acquisition in female rhesus macaques, but the initial mechanisms leading to the induced immunity have not been elucidated. as dendritic cells (dcs) are known to orchestrate both innate and adap ...201931031768
the tat inhibitor didehydro-cortistatin a suppresses siv replication and reactivation.the hiv-1 transactivation protein (tat) binds the hiv mrna transactivation responsive element (tar), regulating transcription and reactivation from latency. drugs against tat are unfortunately not clinically available. we reported that didehydro-cortistatin a (dca) inhibits hiv-1 tat activity. in human cd4+ t cells isolated from aviremic individuals and in the humanized mouse model of latency, combining dca with antiretroviral therapy accelerates hiv-1 suppression and delays viral rebound upon t ...201931021670
dysregulation of sonic hedgehog pathway and pericytes in the brain after lentiviral infection.impairment of the blood-brain barrier (bbb) has been associated with cognitive decline in many cns diseases, including hiv-associated neurocognitive disorders (hand). recent research suggests an important role for the sonic hedgehog (shh) signaling pathway in the maintenance of bbb integrity under both physiological and pathological conditions.201930981282
the frequency of vaccine-induced t-cell responses does not predict the rate of acquisition after repeated intrarectal sivmac239 challenges in mamu-b*08+ rhesus macaques.approximately 50% of rhesus macaques (rms) expressing the major histocompatibility complex class i (mhc-i) allele mamu-b*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (sivmac239) clone. cd8+ t-cell responses in these animals are focused on immunodominant mamu-b*08-restricted siv epitopes in vif and nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in sivmac239-infected mamu-b*08 ...201930541854
comparison of immunogenicity and safety outcomes of a malaria vaccine fmp013/alfq in rhesus macaques (macaca mulatta) of indian and chinese origin.indian-origin rhesus (inr) are preferred for research, but strict export restrictions continue to limit their use. chinese-origin rhesus (chr), although easier to procure, are genetically distinct from inr and differ in their immune response to infectious agents, such as the simian immunodeficiency virus. the most advanced malaria vaccine, rts,s (glaxosmithkline), is based on the circumsporozoite protein (csp) of plasmodium falciparum. the efficacy of rts,s vaccine in the field remains low and s ...201931775762
loneliness in monkeys: neuroimmune mechanisms.loneliness, or perceived social isolation, may be evident in any group-living species, although its assessment in nonhumans provides some measurement challenges. it is well-known that loneliness in humans confers significant risk for morbidity and mortality, although mechanisms remain unclear. the authors describe a naturally-occurring model of loneliness in adult male rhesus monkeys that shows many parallels with the phenomenon in humans. lonely monkeys (those that display high frequencies of s ...201931737750
siv infection aggravates malaria in a chinese rhesus monkey coinfection model.the co-occurrence of human immunodeficiency virus (hiv) infection and malaria in humans in endemic areas raises the question of whether one of these infections affects the course of the other. although epidemiological studies have shown the impact of hiv infection on malaria, the mechanism(s) are not yet fully understood. using a chinese rhesus macaque coinfection model with simian immunodeficiency virus (siv) and plasmodium cynomolgi (pc) malaria, we investigated the effect of concurrent siv in ...201931718574
blocking α4β7 integrin binding to siv does not improve virologic control.a study in nonhuman primates reported that infusions of an antibody against α4β7 integrin, in combination with antiretroviral therapy, showed consistent, durable control of simian immunodeficiency virus (siv) in rhesus macaques. the antibody used has pleiotropic effects, so we set out to gain insight into the underlying mechanism by comparing this treatment to treatment with non-neutralizing monoclonal antibodies against the siv envelope glycoprotein that only block α4β7 binding to siv env but h ...201931488690
quantification of viral rna and dna positive cells in tissues from simian immunodeficiency virus/simian human immunodeficiency virus infected controller and progressor rhesus macaques.eradication of human immunodeficiency virus 1 (hiv-1) from an infected individual cannot be achieved using current antiretroviral therapy (art) regimens. viral reservoirs established in early infection remain unaffected by art and are able to replenish systemic infection upon treatment interruption. simian immunodeficiency virus (siv) infected macaque models are useful for studying hiv pathogenesis, treatments, and persistent viral reservoirs. here, we used the siv macaque model to examine and q ...201931921088
gender differences in innate responses and gene expression profiles in memory cd4 t cells are apparent very early during acute simian immunodeficiency virus infection.gender differences in human immunodeficiency virus (hiv) disease progression and comorbidities have been extensively reported. using the simian immunodeficiency virus (siv) infected rhesus macaque model, we show that these differences are apparent very early during the course of infection. though there were no major changes in the proportions of cd4 t cells or its subsets, central memory cd4 t cells from female macaques were found to differentially regulate a significantly larger number of genes ...201931490965
multivariate profiling of african green monkey and rhesus macaque t lymphocytes.the complexity of immune responses limits the usefulness of univariate methods in answering complex immunology questions. to demonstrate the utility of a multivariate approach, we employ such approach to compare t cells of african green monkeys (agms) and rhesus macaques (rms). among the most prominent distinguishing features we found were lower cd3 and higher cd28 surface expression in agms compared to rms. after in vitro stimulation, a larger proportion of agm t cells secreted cytokines, espec ...201930886198
enhanced transduction of macaca fascicularis hematopoietic cells with chimeric lentiviral vectors.recent marketing approval for genetically engineered hematopoietic stem and t cells bears witness to the substantial improvements in lentiviral vectors over the last two decades, but evaluations of the long-term efficacy and toxicity of gene and cell therapy products will, nevertheless, require further studies in nonhuman primate models. macaca fascicularis monkeys from mauritius have a low genetic diversity and are particularly useful for reproducible drug testing. in particular, they have a ge ...201930848170
macrophage-associated wound healing contributes to african green monkey siv pathogenesis control.natural hosts of simian immunodeficiency virus (siv) avoid aids despite lifelong infection. here, we examined how this outcome is achieved by comparing a natural siv host, african green monkey (agm) to an aids susceptible species, rhesus macaque (rm). to asses gene expression profiles from acutely siv infected agms and rms, we developed a systems biology approach termed conserved gene signature analysis (cgsa), which compared rna sequencing data from rectal agm and rm tissues to various other sp ...201931704931
structural basis for a species-specific determinant of an siv vif protein toward hominid apobec3g antagonism.primate lentiviruses encode a vif protein that counteracts the host antiviral apobec3 (a3) family members. the adaptation of vif to species-specific a3 determinants is a critical event that allowed the spillover of a lentivirus from monkey reservoirs to chimpanzees and subsequently to humans, which gave rise to hiv-1 and the acquired immune deficiency syndrome (aids) pandemic. how vif-a3 protein interactions are remodeled during evolution is unclear. here, we report a 2.94 å crystal structure of ...201931830442
simian immunodeficiency virus infection of rhesus macaques results in delayed zika virus clearance.flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (isgs). how coinfections, particularly simian immunodeficiency viruses (sivs), that induce robust isg signatures influence flavivirus clearance and pathogenesis is unclear. here, we studied how zika virus (zikv) infection is modulated in siv-infected nonhuman primates. we measured zikv replication, cellular zikv rna levels, and immune responses in non-siv-infected and siv-infecte ...201931796542
overexpression of cd6 and pd-1 identifies dysfunctional cd8+ t-cells during chronic siv infection of rhesus macaques.effective cd8+ t-cell responses play an important role in determining the course of siv/hiv viral infection. here we identified a unique population of dysfunctional cd8+ t-cells in lymphoid tissues and bronchoalveolar lavage (bal) of rhesus macaques with chronic siv infection characterized by co-expression of cd6 and pd-1. the frequency of cd6 and pd-1 co-expressing cd8+ t-cells was significantly increased in lymphoid tissues and bal during chronic siv infection compared to pre-infection levels. ...201931998302
statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of hiv-associated pah.pulmonary arterial hypertension (pah) is a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right heart failure. human immunodeficiency virus (hiv)-infected individuals have a higher incidence of pah than the non-hiv infected population and evidence suggests a role for systemic and pulmonary inflammation in the pathogenesis of hiv-associated pah. due to their pleiotropic effects, including immune-modulatory and anti-inflammatory e ...201931882598
vaccination of macaques with dna followed by adenoviral vectors encoding simian immunodeficiency virus (siv) gag alone delays infection by repeated mucosal challenge with siv.vaccines aimed at inducing t cell responses to protect against human immunodeficiency virus (hiv) infection have been under development for more than 15 years. replication-defective adenovirus (rad) vaccine vectors are at the forefront of this work and have been tested extensively in the simian immunodeficiency virus (siv) challenge macaque model. vaccination with rad vectors coding for siv gag or other nonenvelope proteins induces t cell responses that control virus load but disappointingly is ...201931413132
cd8β depletion does not prevent control of viral replication or protection from challenge in macaques chronically infected with a live attenuated simian immunodeficiency virus.we evaluated the contribution of cd8αβ+ t cells to control of live-attenuated simian immunodeficiency virus (lasiv) replication during chronic infection and subsequent protection from pathogenic siv challenge. unlike previous reports with a cd8α-specific depleting monoclonal antibody (mab), the cd8β-specific mab cd8β255r1 selectively depleted cd8αβ+ t cells without also depleting non-cd8+ t cell populations that express cd8α, such as natural killer (nk) cells and γδ t cells. following infusion w ...201931092584
pharmacological modulation of the wnt/β-catenin pathway inhibits proliferation and promotes differentiation of long-lived memory cd4+ t cells in antiretroviral therapy-suppressed simian immunodeficiency virus-infected macaques.the major obstacle to human immunodeficiency type 1 virus (hiv-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (art) and is maintained through cellular proliferation. long-lived memory cd4+ t cells with high self-renewal capacity, such as central memory (cm) t cells and stem cell memory (scm) t cells, are major contributors to the viral reservoir in hiv-infected individuals on art. the wnt/β-catenin signaling pathway regulates the b ...201931619550
role of rhesus macaque ifitm3(2) in simian immunodeficiency virus infection of macaques.the experimental infection of rhesus macaques (rh) with simian immunodeficiency virus (siv) is an important model for human immunodeficiency virus (hiv) infection of humans. the interferon-induced transmembrane protein 3 (ifitm3) inhibits hiv and siv infection at the stage of host cell entry. however, it is still unclear to what extent the antiviral activity of ifitm3 observed in cell culture translates into inhibition of hiv/siv spread in the infected host. we have shown previously that althoug ...201931682595
low-frequency fluctuation characteristics in rhesus macaques with siv infection: a resting-state fmri study.simian immunodeficiency virus (siv)-infected macaque is a widely used model to study human immunodeficiency virus. the purpose of the study is to discover the amplitude of low-frequency fluctuation (alff) and fractional alff (falff) changes in siv-infected macaques. seven rhesus macaques were involved in the longitudinal mri scans: (1) baseline (healthy state); (2) siv infection stage (12 weeks after siv inoculation). alff and falff were subsequently computed and compared to ascertain the change ...201930478797
early t follicular helper cell responses and germinal center reactions are associated with viremia control in immunized rhesus macaques.t follicular helper (tfh) cells are fundamental in germinal center (gc) maturation and selection of antigen-specific b cells within secondary lymphoid organs. gc-resident tfh cells have been fully characterized in human immunodeficiency virus (hiv) infection. however, the role of gc tfh cells in gc b cell responses following various simian immunodeficiency virus (siv) vaccine regimens in rhesus macaques (rms) has not been fully investigated. we characterized gc tfh cells of rms over the course o ...201930463978
mucosal t helper 17 and t regulatory cell homeostasis correlate with acute simian immunodeficiency virus viremia and responsiveness to antiretroviral therapy in macaques.depletion of gut t helper 17 (th17) cells during hiv infection leads to decreased mucosal integrity and increased disease progression. conversely, t regulatory (treg) cells may inhibit antiviral responses or immune activation. in hiv elite controllers, a balanced th17/treg ratio is maintained in the blood, suggesting a role for these responses in controlling inflammation and viral replication. hiv-infected individuals exhibit a range in responsiveness to combination antiretroviral therapy (cart) ...201930398361
dolutegravir monotherapy of simian immunodeficiency virus-infected macaques selects for several patterns of resistance mutations with variable virological outcomes.drug resistance remains a major concern for human immunodeficiency virus (hiv) treatment. to date, very few resistance mutations have emerged in first-line combination therapy that includes the integrase strand transfer inhibitor (insti) dolutegravir (dtg). in vitro, dtg selects for several primary mutations that induce low-level dtg resistance; secondary mutations, while increasing the level of resistance, however, further impair replication fitness, which raised the idea that dtg monotherapy m ...201930381490
monocyte and alveolar macrophage skewing is associated with the development of pulmonary arterial hypertension in a primate model of hiv infection.we investigated the relationship of monocytes, alveolar, and tissue-resident macrophage populations and the development of pulmonary arterial hypertension (pah) in a nonhuman primate model of hiv infection. a prospective study of simian immunodeficiency virus-associated pulmonary arterial hypertension (siv-pah) was done. rhesus macaques (n = 21) were infected with siv. blood, bronchoalveolar lavage fluid (balf), and lung tissue were analyzed for monocyte and macrophage phenotypes and inflammator ...201930229666
oral coadministration of an intramuscular dna/modified vaccinia ankara vaccine for simian immunodeficiency virus is associated with better control of infection in orally exposed infant macaques.the majority of human immunodeficiency virus (hiv) type 1 infections in infants are acquired orally through breastfeeding. toward development of a pediatric hiv vaccine to prevent breastmilk transmission, we tested the efficacy of a simultaneous oral and intramuscular (im) vaccination regimen for preventing oral simian immunodeficiency virus (siv) transmission in infant rhesus macaques. two groups of neonatal macaques were immunized with dna encoding siv virus-like particles (dna-siv) on weeks 0 ...201930303405
bone marrow-derived cd4+ t cells are depleted in simian immunodeficiency virus-infected macaques and contribute to the size of the replication-competent reservoir.the bone marrow (bm) is the key anatomic site for hematopoiesis and plays a significant role in the homeostasis of mature t cells. however, very little is known on the phenotype of bm-derived cd4+ t cells, their fate during simian immunodeficiency virus (siv) infection, and their contribution to viral persistence during antiretroviral therapy (art). in this study, we characterized the immunologic and virologic status of bm-derived cd4+ t cells in rhesus macaques prior to siv infection, during th ...201930305357
in vitro and in vivo models of hiv latency.latently infected cells are very infrequent in cd4+ t cells from antiretroviral (arv) treated individuals, with only approximately one in a million infected cd4+ t cells in blood. given the low frequency of infected cells in vivo, multiple in vitro latency models have been developed to facilitate investigations into mechanisms of hiv latency, as well as to enable the evaluation of pharmacological and immunological interventions aimed at depleting latently infected cells. these in vitro models in ...201930030796
monkey models and hiv vaccine research.since the discovery of acquired immunodeficiency syndrome (aids) in 1981, it has been extremely difficult to develop an effective vaccine or a therapeutic cure despite over 36 years of global efforts. one of the major reasons is due to the lack of an immune-competent animal model that supports live human immunodeficiency virus (hiv) infection and disease progression such that vaccine-induced correlates of protection and efficacy can be determined clearly before human trials. nevertheless, rhesus ...201930030791
mait cells upregulate α4β7 in response to acute simian immunodeficiency virus/simian hiv infection but are resistant to peripheral depletion in pigtail macaques.mucosal-associated invariant t (mait) cells are nonconventional t lymphocytes that recognize bacterial metabolites presented by mr1. whereas gut bacterial translocation and the loss/dysfunction of peripheral mait cells in hiv infection is well described, mait cells in nonhuman primate models are poorly characterized. we generated a pigtail macaque (ptm)-specific mr1 tetramer and characterized mait cells in serial samples from naive and siv- or simian hiv-infected ptm. although ptm mait cells gen ...201930777923
variable baseline papio cynocephalus endogenous retrovirus (pcev) expression is upregulated in acutely siv-infected macaques and correlated to stat1 expression in the spleen.retroviral replication leaves a dna copy in the host cell chromosome, which over millions of years of infection of germline cells has led to 5% of the human genome sequence being comprised of endogenous retroviruses (ervs), distributed throughout an estimated 100,000 loci. over time these loci have accrued mutations such as premature stop codons that prevent continued replication. however, many loci remain both transcriptionally and translationally active and ervs have been implicated in interac ...201931156613
a longitudinal molecular study of the ecology of malaria infections in free-ranging mandrills.unravelling the determinants of host variation in susceptibility and exposure to parasite infections, infection dynamics and the consequences of parasitism on host health is of paramount interest to understand the evolution of complex host-parasite interactions. in this study, we evaluated the determinants, temporal changes and physiological correlates of plasmodium infections in a large natural population of mandrills (mandrillus sphinx). over six consecutive years, we obtained detailed parasit ...201931667087
genome-wide patterns of gene expression in a wild primate indicate species-specific mechanisms associated with tolerance to natural simian immunodeficiency virus infection.over 40 species of nonhuman primates host simian immunodeficiency viruses (sivs). in natural hosts, infection is generally assumed to be nonpathogenic due to a long coevolutionary history between host and virus, although pathogenicity is difficult to study in wild nonhuman primates. we used whole-blood rna-seq and siv prevalence from 29 wild ugandan red colobus (piliocolobus tephrosceles) to assess the effects of siv infection on host gene expression in wild, naturally siv-infected primates. we ...201931106820
low postseroconversion cd4+ t-cell level is associated with faster disease progression and higher viral evolutionary rate in hiv-2 infection.a positive correlation between virus evolutionary rate and disease progression has been shown for human immunodeficiency virus type 1 (hiv-1) infection. much less is known about hiv-2, the second causative agent of aids. we analyzed 528 hiv-2 env v1-c3 sequences generated from longitudinal plasma samples that were collected from 16 study participants during a median observation time of 7.9 years (interquartile range [iqr], 5.2 to 14.0 years). study participants were classified as faster or slowe ...201930622192
modified newcastle disease virus as an improved vaccine vector against simian immunodeficiency virus.siv infection in macaques is a relevant animal model for hiv pathogenesis and vaccine study in humans. to design a safe and effective vaccine against hiv, we evaluated the suitability of naturally-occurring avirulent newcastle disease virus (ndv) strains and several modified versions of ndv as vectors for the expression and immunogenicity of siv envelope protein gp160. all the ndv vectors expressed gp160 protein in infected cells. the gp160 expressed by these vectors formed oligomers and was inc ...201829895833
noninvasive western lowland gorilla's health monitoring: a decade of simian immunodeficiency virus surveillance in southern cameroon.simian immunodeficiency virus (sivgor) causes persistent infection in critically endangered western lowland gorillas (gorilla gorilla gorilla) from west central africa. sivgor is closely related to chimpanzee and human immunodeficiency viruses (sivcpz and hiv-1, respectively). we established a noninvasive method that does not interfere with gorillas' natural behaviour to provide wildlife pathogen surveillance and health monitoring for conservation. a total of 1,665 geo-referenced fecal samples w ...201830519399
analysis of complement-mediated lysis of simian immunodeficiency virus (siv) and siv-infected cells reveals sex differences in vaccine-induced immune responses in rhesus macaques.an effective human immunodeficiency virus (hiv) vaccine has yet to be developed, and defining immune correlates of protection against hiv infection is of paramount importance to inform future vaccine design. the complement system is a component of innate immunity that can directly lyse pathogens and shape adaptive immunity. to determine if complement lysis of simian immunodeficiency virus (siv) and/or siv-infected cells represents a protective immune correlate against siv infection, sera from pr ...201830021899
t-cell subset differentiation and antibody responses following antiretroviral therapy during simian immunodeficiency virus infection.antiretroviral therapy (art) for the treatment of human immunodeficiency virus (hiv) infection represents a major breakthrough in the treatment of hiv/acquired immune-deficiency syndrome. however, it remains unclear how art influences virus-specific immune responses and understanding this is important for developing novel cure and eradication interventions for hiv-1. in the present study, we evaluate how art impacts t-cell and antibody responses in simian immunodeficiency virus (siv) -infected r ...201830014618
baboon cd8 t cells suppress sivmac infection in cd4 t cells through contact-dependent production of mip-1α, mip-1β, and rantes.simian immunodeficiency virus (siv) infection in rhesus macaques is often characterized by high viremia and cd4 t cell depletion. by contrast, siv infection in african nonhuman primate natural hosts is typically nonpathogenic despite active viral replication. baboons are abundant in africa and have a geographical distribution that overlaps with natural hosts, but they do not harbor sivs. previous work has demonstrated baboons are resistant to chronic siv infection and/or disease in vivo but the ...201829807688
short-term pegylated interferon α2a treatment does not significantly reduce the viral reservoir of simian immunodeficiency virus-infected, antiretroviral therapy-treated rhesus macaques.the major obstacle to human immunodeficiency type 1 (hiv-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (art) and causes rapid viral rebound if treatment is interrupted. type i interferons are immunomodulatory cytokines that induce antiviral factors and have been evaluated for the treatment of hiv-infected individuals, resulting in moderate reduction of viremia and inconclusive data about their effect on reservoir size. here, we as ...201829720521
marginal effects of systemic ccr5 blockade with maraviroc on oral simian immunodeficiency virus transmission to infant macaques.current approaches do not eliminate all human immunodeficiency virus type 1 (hiv-1) maternal-to-infant transmissions (mtit); new prevention paradigms might help avert new infections. we administered maraviroc (mvc) to rhesus macaques (rms) to block ccr5-mediated entry, followed by repeated oral exposure of a ccr5-dependent clone of simian immunodeficiency virus (siv) mac251 (sivmac766). mvc significantly blocked the ccr5 coreceptor in peripheral blood mononuclear cells and tissue cells. all cont ...201829925666
correlates of protection against sivmac251 infection in rhesus macaques immunized with chimpanzee-derived adenovirus vectors.we report on prime-boost vaccine regimens with two simian adenovirus (ad) vectors (sadv) or two human serotype ad vectors (hadv) expressing gag and gp160 of simian immunodeficiency virus (siv)mac239 tested in hadv-seropositive rhesus macaques (rms) repeatedly challenged rectally with low doses of sivmac251. both vaccine regimens reduced set point and peak viral loads (pvl) and accelerated viral clearance. in sadv-vaccinated controller genotype rms resistance against infection correlated with lev ...201829685793
impaired development and expansion of germinal center follicular th cells in simian immunodeficiency virus-infected neonatal macaques.germinal center (gc) cd4+ follicular th (tfh) cells are critical for cognate b cell help in humoral immune responses to pathogenic infections. although tfh cells are expanded or depleted in hiv/siv-infected adults, the effects of pediatric hiv/siv infection on tfh cells remain unclear. in this study, we examined changes in lymphoid follicle formation in lymph nodes focusing on gc tfh cells, b cell development, and differentiation in siv-infected neonatal rhesus macaques (macaca mulatta) compared ...201830104244
early antiretroviral therapy limits siv reservoir establishment to delay or prevent post-treatment viral rebound.prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (rhcmv) vectors expressing simian immunodeficiency virus (siv) antigens (rhcmv/siv) elicits immune responses that stringently control highly pathogenic siv infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. in contrast, here, we show that therapeutic rhcmv/siv vaccination of rhesus macaques previously infected with siv and given continuous combination antiretroviral therapy (cart) beginning ...201830082858
tlr7 agonists induce transient viremia and reduce the viral reservoir in siv-infected rhesus macaques on antiretroviral therapy.antiretroviral therapy (art) can halt hiv-1 replication but fails to target the long-lived latent viral reservoir. several pharmacological compounds have been evaluated for their ability to reverse hiv-1 latency, but none has demonstrably reduced the latent hiv-1 reservoir or affected viral rebound after the interruption of art. we evaluated orally administered selective toll-like receptor 7 (tlr7) agonists gs-986 and gs-9620 for their ability to induce transient viremia in rhesus macaques infec ...201829720451
effects of an actriib.fc ligand trap on cardiac function in simian immunodeficiency virus-infected male rhesus macaques.an important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. the current study evaluated the effects of a soluble actriib receptor fc fusion protein (actriib.fc), a ligand trap for tgf-β/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (siv)-infected juvenile rhesus macaques (macaca mulatta). fourteen pair-housed, juvenile male rhe ...201830019021
dynamics of simian immunodeficiency virus two-long-terminal-repeat circles in the presence and absence of cd8+ cells.cd8+ cells play a key role in human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) infection, but their specific mechanism(s) of action in controlling the virus is unclear. two-long-terminal-repeat (2-ltr) circles are extrachromosomal products generated upon failed integration of hiv/siv. to understand the specific effects of cd8+ cells on infected cells, we analyzed the dynamics of 2-ltr circles in sivmac251-infected rhesus macaques (rms) treated with an integrase inhibitor (i ...201829643246
simian immunodeficiency virus vif and human apobec3b interactions resemble those between hiv-1 vif and human apobec3g.several members of the apobec3 dna cytosine deaminase family can potently inhibit vif-deficient human immunodeficiency virus type 1 (hiv-1) by catalyzing cytosine deamination in viral cdna and impeding reverse transcription. hiv-1 counteracts restriction with the virally encoded vif protein, which targets relevant apobec3 proteins for proteasomal degradation. hiv-1 vif is optimized for degrading the restrictive human apobec3 repertoire, and, in general, lentiviral vif proteins specifically targe ...201829618650
gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with siv or shiv.human gammaherpesviruses are associated with malignancies in hiv infected individuals; in macaques used in non-human primate models of hiv infection, gammaherpesvirus infections also occur. limited data on prevalence and tumorigenicity of macaque gammaherpesviruses, mostly cross-sectional analyses of small series, are available. we comprehensively examine all three-rhesus macaque gammaherpesviruses -rhesus rhadinovirus (rrv), rhesus lymphocryptovirus (rlcv) and retroperitoneal fibromatosis herpe ...201830001436
simian immunodeficiency virus persistence in cellular and anatomic reservoirs in antiretroviral therapy-suppressed infant rhesus macaques.worldwide, nearly two million children are infected with human immunodeficiency virus (hiv), with breastfeeding accounting for the majority of contemporary hiv transmissions. antiretroviral therapy (art) has reduced hiv-related morbidity and mortality but is not curative. the main barrier to a cure is persistence of latent hiv in long-lived reservoirs. however, our understanding of the cellular and anatomic sources of the hiv reservoir during infancy and childhood is limited. here, we developed ...201829997216
cd24 and fc fusion protein protects sivmac239-infected chinese rhesus macaque against progression to aids.chronic immune activation and systemic inflammation are underlying causes of acquired immunodeficiency syndrome (aids). products of virus replication and microbial translocation, co-infection or opportunistic pathogens, and danger-associated molecular patterns have been reported to contribute to chronic immune activation and inflammation in human immunodeficiency virus type-1/simian immunodeficiency virus (hiv-1/siv) infection or other disease. to develop new strategies and therapies for hiv-1/a ...201829983395
a bistable switch in virus dynamics can explain the differences in disease outcome following siv infections in rhesus macaques.experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. the possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. in this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. the model e ...201829930544
control of heterologous simian immunodeficiency virus sivsme660 infection by dna and protein coimmunization regimens combined with different toll-like-receptor-4-based adjuvants in macaques.we developed a method of simultaneous vaccination with dna and protein resulting in robust and durable cellular and humoral immune responses with efficient dissemination to mucosal sites and protection against simian immunodeficiency virus (siv) infection. to further optimize the dna-protein coimmunization regimen, we tested a sivmac251-based vaccine formulated with either of two toll-like receptor 4 (tlr4) ligand-based liposomal adjuvant formulations (tlr4 plus tlr7 [tlr4+7] or tlr4 plus qs21 [ ...201829793957
temporal/compartmental changes in viral rna and neuronal injury in a primate model of neuroaids.despite the advent of highly active anti-retroviral therapy hiv-associated neurocognitive disorders (hand) continue to be a significant problem. furthermore, the precise pathogenesis of this neurodegeneration is still unclear. the objective of this study was to examine the relationship between infection by the simian immunodeficiency virus (siv) and neuronal injury in the rhesus macaque using in vivo and postmortem sampling techniques. the effect of siv infection in 23 adult rhesus macaques was ...201829750804
a simultaneous oral and intramuscular prime/sublingual boost with a dna/modified vaccinia ankara viral vector-based vaccine induces simian immunodeficiency virus-specific systemic and mucosal immune responses in juvenile rhesus macaques.a pediatric vaccine to prevent breast milk transmission of human immunodeficiency virus (hiv) may generate greater immune responses at viral entry sites if given by an oral route.201830204253
antibody-mediated cd4 depletion induces homeostatic cd4+ t cell proliferation without detectable virus reactivation in antiretroviral therapy-treated simian immunodeficiency virus-infected macaques.a major barrier to human immunodeficiency virus (hiv) eradication is the long-term persistence of latently infected cd4+ t cells harboring integrated replication-competent virus. it has been proposed that the homeostatic proliferation of these cells drives long-term reservoir persistence in the absence of virus reactivation, thus avoiding cell death due to either virus-mediated cytopathicity or immune effector mechanisms. here, we conducted an experimental depletion of cd4+ t cells in eight anti ...201830185596
polymorphisms in rhesus macaque tetherin are associated with differences in acute viremia in simian immunodeficiency virus δnef-infected animals.tetherin (bst-2 or cd317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. to determine the extent of sequence variation and the impact of polymorphisms in rhesus macaque tetherin on simian immunodeficiency virus (siv) infection, tetherin alleles were sequenced from 146 rhesus macaques, including 68 animals infected with wild-type sivmac239 and 47 animals infected with sivmac239δnef since nef is the viral gene product of siv that counteracts restr ...201830135127
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