| respiratory tract explant infection dynamics of influenza a virus in california sea lions, northern elephant seals, and rhesus macaques. | to understand susceptibility of wild california sea lions and northern elephant seals to influenza a virus (iav), we developed an ex vivo respiratory explant model and used it to compare infection kinetics for multiple iav subtypes. we first established the approach using explants from colonized rhesus macaques, a model for human iav. trachea, bronchi, and lungs from 11 california sea lions, 2 northern elephant seals, and 10 rhesus macaques were inoculated within 24 h postmortem with 6 strains r ... | 2021 | 34037419 |
| host-cell dependent role of phosphorylated keratin 8 during influenza a/nws/33 virus (h1n1) infection in mammalian cells. | in this study, we investigated the involvement of keratin 8 during human influenza a/nws/33 virus (h1n1) infection in semi-permissive rhesus monkey-kidney (llc-mk2) and permissive human type ii alveolar epithelial (a549) cells. in a549 cells, keratin 8 showed major expression and phosphorylation levels. influenza a/nws/33 virus was able to subvert keratin 8 structural organization at late stages of infection in both cell models, promoting keratin 8 phosphorylation in a549 cells at early phases o ... | 2021 | 33556415 |
| development of a simian rna polymerase i promoter-driven reverse genetics for the rescue of recombinant rift valley fever virus from vero cells. | rift valley fever (rvf), which has been designated as a priority disease by the world health organization (who), is one of the most pathogenic zoonotic diseases endemic to africa and the arabian peninsula. human vaccine preparation requires the use of appropriate cell substrates to support efficient production of seed vaccine with minimum concerns of tumorigenicity, oncogenicity, or adventitious agents. vero cells, which were derived from the african green monkey kidney, represent one of the few ... | 2021 | 33441343 |
| oral vaccination approaches for anti-shiv immunity. | we modified a sabin oral poliovirus vaccine (opv) vector to permit secretion of the antigens of interest with the goal of improving anti-hiv env humoral responses in a shiv mucosal immunization composed of dna and recombinant opvs. we evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in rhesus macaques by two regimens, both involving a prime with a shivbg505 dna construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral ... | 2021 | 34234789 |
| luminal microvesicles uniquely influence translocating bacteria after siv infection. | microbial translocation contributes to persistent inflammation in both treated and untreated hiv infection. although translocation is due in part to a disintegration of the intestinal epithelial barrier, there is a bias towards the translocation of proteobacteria. we hypothesized that intestinal epithelial microvesicle cargo differs after hiv infection and contributes to biased translocation. we isolated gastrointestinal luminal microvesicles before and after progressive simian immunodeficiency ... | 2021 | 33731830 |
| development and evaluation of a rapid and cost-efficient ngs-based mhc class i genotyping method for macaques by using a prevalent short-read sequencer. | rhesus macaque is one of the most widely used primate model animals for immunological research of infectious diseases including human immunodeficiency virus (hiv) infection. it is well known that major histocompatibility complex (mhc) class i genotypes affect the susceptibility and disease progression to simian immunodeficiency virus (siv) in rhesus macaques, which is resembling to hiv in humans. it is required to convincingly determine the mhc genotypes in the immunological investigations, that ... | 2021 | 33447871 |
| monitoring immune activation with whole-body fluorodeoxyglucose-positron-emission tomography in simian immunodeficiency virus-infected rhesus macaques. | this study aimed to assess immune activation in tissues by measuring glucose metabolism with 18f-fluorodeoxyglucose (fdg) and investigate the associations of various peripheral markers of disease progression with initiation and interruption of combination antiretroviral therapy in siv-infected rhesus macaques (macaca mulatta). mixed-effect linear models revealed a significant inverse association of peripheral blood cd4+ t cell counts (p < 0.01) and a direct association of plasma viral load (p < ... | 2021 | 34282030 |
| vaccine nanodiscs plus polyiclc elicit robust cd8+ t cell responses in mice and non-human primates. | conventional cancer vaccines based on soluble vaccines and traditional adjuvants have produced suboptimal therapeutic efficacy in clinical trials. thus, there is an urgent need for vaccine technologies that can generate potent t cell responses with strong anti-tumor efficacy. we have previously reported the development of synthetic high-density protein (shdl) nanodiscs for efficient lymph node (ln)-targeted co-delivery of antigen peptides and cpg oligonucleotides (a toll-like receptor-9 agonist) ... | 2021 | 34280415 |
| invaplex functions as an intranasal adjuvant for subunit and dna vaccines co-delivered in the nasal cavity of nonhuman primates. | development of intranasal vaccines for hiv-1 and other mucosal pathogens has been hampered by the lack of adjuvants that can be given safely to humans. we have found that an intranasal shigella vaccine (invaplex) which is well tolerated in humans can also function as an adjuvant for intranasal protein and dna vaccines in mice. to determine whether invaplex could potentially adjuvant similar vaccines in humans, we simultaneously administered a simian immunodeficiency virus (siv) envelope (env) pr ... | 2021 | 34258576 |
| late-phase dominance of a single epitope-specific cd8+ t-cell response in passive neutralizing antibody-infused siv controllers. | analysis of the quantity and quality of epitope-specific cd8+ t-cell responses is crucial for understanding the mechanism of hiv/simian immunodeficiency virus (siv) replication control. we have previously shown that acute-phase passive infusion of neutralizing antibodies (nabs) results in augmented broad t-cell responses and robust sivmac239 control in rhesus macaques. analyzing long-term dynamics of cd8+ t-cell responses in these siv controllers provides important insights into designing lastin ... | 2021 | 34224443 |
| neutralizing antibody induction associated with a germline immunoglobulin gene polymorphism in neutralization-resistant sivsme543-3 infection. | antibody responses are crucial for the control of virus infection. understanding of the mechanism of antibody induction is important for the development of a vaccine eliciting effective anti-virus antibodies. virus-specific b cell receptor (bcr)/antibody repertoires are different among individuals, but determinants for this difference remain largely unclear. we have recently reported that a germline bcr immunoglobulin (igg) gene polymorphism (vh3.33_et or vh3.33_vi) in rhesus macaques is the det ... | 2021 | 34205728 |
| viremia controls env-specific antibody-secreting cell responses in siv-infected macaques pre- and post-art. | to investigate the kinetics of env (gp140)-specific antibody-secreting cells (ascs) during acute and early chronic simian immunodeficiency virus (siv) infection, and prior to and post-antiretroviral therapy (art) in rhesus macaques (rms). | 2021 | 34148985 |
| lack of specific regulatory t cell depletion and cytoreduction associated with extensive toxicity after administration of low and high doses of cyclophosphamide. | up to 93% of the human immunodeficiency virus (hiv) latent reservoir comprised defective proviruses, suggesting that a functional cure is possible through the elimination of a small population of cells containing intact virus, instead of the entire reservoir. cyclophosphamide (cy) is an established chemotherapeutic agent for immune cell cancers. in high doses, cy is a nonselective cytoreductor, used in allogeneic stem-cell transplantation, while in a low dose, metronomic schedule, cy selectively ... | 2021 | 33957772 |
| enhanced intestinal tgf-β/smad-dependent signaling in simian immunodeficiency virus infected rhesus macaques. | transforming growth factor-β signaling (tgf-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either smad2/3 and smad7 (smad-dependent) or smad-independent signaling pathways under normal conditions. increased production of tgf-β promotes immunosuppression in human immunodeficiency virus (hiv)/simian immunodeficiency virus (siv) infection. however, the cellular source and downstream events of inc ... | 2021 | 33916615 |
| recombinant herpesvirus vectors: durable immune responses and durable protection against simian immunodeficiency virus sivmac239 acquisition. | a prophylactic vaccine that confers durable protection against human immunodeficiency virus (hiv) would provide a valuable tool to prevent new hiv/aids cases. as herpesviruses establish lifelong infections that remain largely subclinical, the use of persistent herpesvirus vectors to deliver hiv antigens may facilitate the induction of long-term anti-hiv immunity. we previously developed recombinant (r) forms of the gamma-herpesvirus rhesus monkey rhadinovirus (rrrv) expressing a replication-inco ... | 2021 | 33910957 |
| human immunodeficiency virus-1/simian immunodeficiency virus infection induces opening of pannexin-1 channels resulting in neuronal synaptic compromise: a novel therapeutic opportunity to prevent neurohiv. | in healthy conditions, pannexin-1 (panx-1) channels are in a close state, but in several pathological conditions, including human immunodeficiency virus-1 (hiv) and neurohiv, the channel becomes open. however, the mechanism or contribution of panx-1 channels to the hiv pathogenesis and neurohiv is unknown. to determine the contribution of panx-1 channels to the pathogenesis of neurohiv, we used a well-established model of simian immunodeficiency virus (siv) infection in macaques (macaca mulatta) ... | 2021 | 33899944 |
| antiretroviral therapy administration reduces neuroinflammation without restoring brain-derived neurotrophic factor signaling in alcohol-administered simian immunodeficiency virus-infected macaques. | the present study examined interactions between simian immunodeficiency virus (siv), chronic binge alcohol (cba), and antiretroviral therapy (art) on growth factor signaling, neuroinflammatory markers, viral loads (vl), and cd4+ cell counts. | 2021 | 33813553 |
| dimethyl fumarate, an approved multiple sclerosis treatment, reduces brain oxidative stress in siv-infected rhesus macaques: potential therapeutic repurposing for hiv neuroprotection. | dimethyl fumarate (dmf), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. we hypothesized that dmf administration to simian immunodeficiency virus (siv)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. nine siv-infected, cd8+-t-lymphocyte-depleted rhesus macaques were studied. five received oral dmf ... | 2021 | 33803289 |
| non-neutralizing antibodies may contribute to suppression of sivmac239 viremia in indian rhesus macaques. | the antiviral properties of broadly neutralizing antibodies against hiv are well-documented but no vaccine is currently able to elicit protective titers of these responses in primates. while current vaccine modalities can readily induce non-neutralizing antibodies against simian immunodeficiency virus (siv) and hiv, the ability of these responses to restrict lentivirus transmission and replication remains controversial. here, we investigated the antiviral properties of non-neutralizing antibodie ... | 2021 | 33796119 |
| chronic opioid administration is associated with prevotella-dominated dysbiosis in sivmac251 infected, cart-treated macaques. | people living with the human immunodeficiency virus (hiv) have an elevated risk of opioid misuse due to both prescriptions for hiv-associated chronic pain and because injection drug use remains a primary mode of hiv transmission. hiv pathogenesis is characterized by chronic immune activation and microbial dysbiosis, and translocation across the gut barrier exacerbating inflammation. despite the high rate of co-occurrence, little is known about the microbiome during chronic opioid use in the cont ... | 2021 | 33788119 |
| hla-e-restricted, gag-specific cd8+ t cells can suppress hiv-1 infection, offering vaccine opportunities. | human leukocyte antigen-e (hla-e) normally presents an hla class ia signal peptide to the nkg2a/c-cd94 regulatory receptors on natural killer (nk) cells and t cell subsets. rhesus macaques immunized with a cytomegalovirus-vectored simian immunodeficiency virus (siv) vaccine generated mamu-e (hla-e homolog)-restricted t cell responses that mediated post-challenge siv replication arrest in >50% of animals. however, hiv-1-specific, hla-e-restricted t cells have not been observed in hiv-1-infected i ... | 2021 | 33766848 |
| comparison of predictors for terminal disease progression in simian immunodeficiency virus/simian-hiv-infected rhesus macaques. | cd4+ t-cell decline and increasing virus levels are considered hallmarks of hiv/aids pathogenesis but we previously demonstrated in rhesus macaques that tissue macrophage destruction by simian immunodeficiency virus (siv) infection associated with increased monocyte turnover also appear to impact pathogenesis. it remains unclear, however, which factors best predict onset of terminal disease progression and survival time. the objective of this study, therefore, was to directly compare these co-va ... | 2021 | 33710021 |
| two human monoclonal hla-reactive antibodies cross-react with mamu-b*008, a rhesus macaque mhc allotype associated with control of simian immunodeficiency virus replication. | mhc class i molecules play an important role in adaptive immune responses against intracellular pathogens. these molecules are highly polymorphic, and many allotypes have been characterized. in a transplantation setting, a mismatch between mhc allotypes may initiate an alloimmune response. rhesus macaques (macaca mulatta, mamu) are valuable as a preclinical model species in transplantation research as well as to evaluate the safety and efficacy of vaccine candidates. in both lines of research, t ... | 2021 | 33692147 |
| development of a reverse transcription droplet digital pcr (rt-ddpcr) assay for sensitive detection of simian immunodeficiency virus (siv). | simian immunodeficiency virus (siv)-infected rhesus macaques constitute an excellent model of human hiv infection. sensitive detection of siv rna in cell and tissue samples from infected animals subjected to treatment regimens becomes especially critical in determining which therapeutic attempts are successful, and consequently, which interventions should be prioritized in hiv cure research. | 2021 | 33588884 |
| immune responses and viral persistence in simian/human immunodeficiency virus shiv.c.ch848-infected rhesus macaques. | chimeric simian/human immunodeficiency viruses (shivs) are widely used in nonhuman primate models to recapitulate human immunodeficiency virus (hiv) infection in humans, yet most shivs fail to establish persistent viral infection. we investigated immunological and virological events in rhesus macaques infected with the newly developed shiv.c.ch848 (shivc) and treated with combined antiretroviral therapy (cart). similar to hiv/simian immunodeficiency virus (siv) infection, shiv.c.ch848 infection ... | 2021 | 33568508 |
| combining in vivo corneal confocal microscopy with deep learning-based analysis reveals sensory nerve fiber loss in acute simian immunodeficiency virus infection. | to characterize corneal subbasal nerve plexus features of normal and simian immunodeficiency virus (siv)-infected macaques by combining in vivo corneal confocal microscopy (ivcm) with automated assessments using deep learning-based methods customized for macaques. | 2021 | 33528225 |
| a potent anti-simian immunodeficiency virus neutralizing antibody induction associated with a germline immunoglobulin gene polymorphism in rhesus macaques. | virus infection induces b cells with a wide variety of b cell receptor (bcr) repertoires. patterns of induced bcr repertoires are different in individuals, while the underlying mechanism causing this difference remains largely unclear. in particular, the impact of germ line bcr immunoglobulin (ig) gene polymorphism on b cell/antibody induction has not fully been determined. in the present study, we found a potent antibody induction associated with a germ line bcr ig gene polymorphism. b404-class ... | 2021 | 33441342 |
| increased proviral dna in circulating cells correlates with plasma viral rebound in simian immunodeficiency virus-infected rhesus macaques after antiretroviral therapy interruption. | the human immunodeficiency virus (hiv) reservoir is responsible for persistent viral infection, and a small number of mosaic latent cellular reservoirs promote viral rebound upon antiretroviral therapy interruption, which is the major obstacle to a cure. however, markers that determine effective therapy and viral rebound posttreatment interruption remain unclear. in this study, we comprehensively and longitudinally tracked dynamic decay of cell-associated viral rna/dna in systemic and lymphoid t ... | 2021 | 33408173 |
| brain tissue transcriptomic analysis of siv-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis and poly (adp-ribose) polymerases (parps) as potential therapeutic targets. | despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (hiv-1)-associated neurocognitive disorders (hand) remain prevalent in subjects undergoing therapy. hand significantly affects individuals' quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. we investigated transcriptomic profiles in frontal cortex tissues of simian immunodeficiency vi ... | 2021 | 33405206 |
| pharmacokinetics and immunological effects of romidepsin in rhesus macaques. | hiv/siv persistence in latent reservoirs requires lifelong antiretroviral treatment and calls for effective cure strategies. romidepsin (rmd), a histone deacetylase inhibitor, was reported to reactivate hiv/siv from reservoirs in virus-suppressed individuals. we characterized in detail the pharmacokinetics and safety profile of rmd in three siv-naïve rhesus macaques which received two rounds of treatment. in plasma, rmd mean terminal half-life was 15.3 h. in comparison, rmd mean terminal half-li ... | 2020 | 33362765 |
| high-resolution quantitative mapping of macaque cervicovaginal epithelial thickness: implications for mucosal vaccine delivery. | vaginal mucosal surfaces naturally offer some protection against sexually transmitted infections (stis) including human immunodeficiency virus-1, however topical preventative medications or vaccine designed to boost local immune responses can further enhance this protection. we previously developed a novel mucosal vaccine strategy using viral vectors integrated into mouse dermal epithelium to induce virus-specific humoral and cellular immune responses at the site of exposure. since vaccine integ ... | 2021 | 34262561 |
| immunoprofiling correlates of protection against shiv infection in adjuvanted hiv-1 pox-protein vaccinated rhesus macaques. | human immunodeficiency virus type 1 (hiv-1) infection remains a major public health threat due to its incurable nature and the lack of a highly efficacious vaccine. the rv144 vaccine trial is the only clinical study to date that demonstrated significant but modest decrease in hiv infection risk. to improve hiv-1 vaccine immunogenicity and efficacy, we recently evaluated pox-protein vaccination using a next generation liposome-based adjuvant, army liposomal formulation adsorbed to aluminum (alfa) ... | 2021 | 34046030 |
| exploration of a sequential gp140-gp145 immunization regimen with heterologous envs to induce a protective cross-reactive hiv neutralizing antibody response in non-human primates. | raising a heterologous tier 2 neutralizing antibody (nab) response remains a daunting task for hiv vaccine development. in this study, we explored the utility of diverse hiv-1 envelope (env) immunogens in a sequential immunization scheme as a solution to this task. this exploration stemmed from the rationale that gp145, a membrane-bound truncation form of hiv env, may facilitate the focusing of induced antibody response on neutralizing epitopes when sequentially combined with the soluble gp140 f ... | 2021 | 33723807 |
| human trim5α: autophagy connects cell-intrinsic hiv-1 restriction and innate immune sensor functioning. | human immunodeficiency virus-1 (hiv-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. combination antiretroviral treatment is highly effective, but hiv-1 patients that have been treated still suffer from chronic inflammation and residual viral replication. it is therefore paramount to identify therapeutically efficacious strategies to eradicate viral reservoirs and ultimately develop a cure for hiv-1. it ... | 2021 | 33669846 |