Selected Grantee Publications
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- 179 results found
- Nonhuman Primate Models
- Immunology
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
SIV Infection Is Associated With Transient Acute-Phase Steatosis in Hepatocytes In Vivo
Derby, Viruses. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10892327/
Metabolic dysfunction–associated fatty liver disease (MAFLD) in people with HIV has become an increasing concern, but little is known about liver-specific changes underlying HIV-related MAFLD. Using rhesus macaques (sex not specified), researchers examined the timing of pathogenic changes within the liver during simian immunodeficiency virus (SIV) infection. Their findings suggest differential pathologies associated with the acute and chronic phases of infection. This work highlights the early damage inflicted on the liver by SIV/HIV infection and indicates that damage to the hepatocytes plays a specific role. Overall, the authors conclude that therapeutic interventions targeting metabolic function may benefit liver health in people who have recently received an HIV diagnosis. Supported by ORIP (P51OD011107, P51OD011092) and NIAID.
Consistent Survival in Consecutive Cases of Life-Supporting Porcine Kidney Xenotransplantation Using 10GE Source Pigs
Eiseson et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/38637524/
Xenotransplantation offers potential for addressing organ donor shortages, and the U.S. Food and Drug Administration recently issued guidance on a regulatory path forward. Researchers have performed studies in this area, but concerns have been expressed about safe clinical translation of their results (e.g., survival, preclinical procurement, immunosuppression, clinical standards of care). In this study, the authors report consistent survival in consecutive cases of kidney xenotransplantation from pigs (male and female) to baboons (male and female). The authors propose that their findings serve as proof of concept for prevention of xenograft rejection in recipients of genetically modified porcine kidneys. This work offers insights for immunosuppression regimens for first-in-human clinical trials. Supported by ORIP (P40OD024628).
Potent Antibody-Dependent Cellular Cytotoxicity of a V2-Specific Antibody Is Not Sufficient for Protection of Macaques Against SIV Challenge
Grunst et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38252675/
Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with decreased risk of HIV acquisition. Researchers tested the ability of PGT145, an antibody that neutralizes genetically diverse HIV-1 isolates, to protect rhesus macaques against simian immunodeficiency virus (SIV) via ADCC activity. They found that a single amino acid substitution in the V2 core epitope of the SIV envelope increases PGT145 binding and confers sensitivity to neutralization. Peak and chronic phase viral loads were lower, and time to peak viremia was delayed. They concluded that ADCC is insufficient for protection by this antibody, but increasing the affinity of antibody binding could confer partial protection. Supported by ORIP (P51OD011106), NIAID, and NCI.
SHIV-C109p5 NHP Induces Rapid Disease Progression in Elderly Macaques with Extensive GI Viral Replication
Bose et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38299866/
Researchers are interested in developing animal models infected with simian–human immunodeficiency virus (SHIV) to better understand prevention of HIV acquisition. Researchers generated pathogenic SHIV clade C transmitted/founder stock by in vivo passage using geriatric rhesus macaques of both sexes. They reported that the infection resulted in high sustained viral loads and induced rapid pathology and wasting, necessitating euthanasia between 3 and 12 weeks post-infection. The extensive viral replication in gut and lymphoid tissues indicated a fit viral stock. This work provides a new nonhuman primate model for HIV pathogenicity and cure studies. Supported by ORIP (R24OD010947) and NIDDK.
Induction of Durable Remission by Dual Immunotherapy in SHIV-Infected ART-Suppressed Macaques
Lim et al., Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/38422185/
The latent viral reservoir is established within the first few days of HIV infection and remains a barrier to a clinical cure. Researchers characterized the effects of a combined Anktiva (N-803) treatment with broadly neutralizing antibodies (bNAbs) using male and female rhesus macaques infected with simian–human immunodeficiency virus infection. Their data suggest that these agents synergize to enhance CD8+ T-cell function, particularly when multiple bNAbs are used. Taken together, this work indicates that immune-mediated control of viral rebound is not a prerequisite for sustained remission after discontinuation of antiretroviral therapy and that immune-mediated control of viral rebound is achievable, sufficient, and sustainable in this model. Supported by ORIP (P51OD011106, P40OD028116, R24OD011195) and NIAID.
Trade-Offs Shaping Transmission of Sylvatic Dengue and Zika Viruses in Monkey Hosts
Hanley et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/38538621/
Mosquito-borne dengue (DENV) and Zika (ZIKV) viruses originated in Old World sylvatic (forest) cycles involving monkeys and canopy-living Aedes mosquitoes. Both viruses spilled over into human transmission and were translocated to the Americas, opening a path for spillback into neotropical sylvatic cycles. This article reports that the trade-offs that shape within-host dynamics and transmission of these viruses are lacking, hampering efforts to predict spillover and spillback. The data revealed evidence of an immunologically mediated trade‑off between duration and magnitude of virus replication, as higher-peak ZIKV titers are associated with shorter durations of viremia, and higher natural killer cell levels are associated with lower peak ZIKV titers and lower anti-DENV-2 antibody levels. Furthermore, patterns of transmission of each virus from a neotropical monkey suggest that ZIKV has greater potential than DENV-2 to establish a sylvatic transmission cycle in the Americas. Supported by ORIP (P40OD010938) and NIAID.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
Antibiotic-Induced Gut Dysbiosis Elicits Gut–Brain–Axis Relevant Multi-Omic Signatures and Behavioral and Neuroendocrine Changes in a Nonhuman Primate Model
Hayer et al., Gut Microbes. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826635/
Gut microbiome–mammalian cell interactions influence the development of metabolic, immune-mediated, and neuropsychiatric disorders. Dysbiosis of the gut microbiome has been linked to behavioral characteristics in previous nonhuman primate (NHP) studies, but additional studies using NHPs are necessary to understand microbiota–gut–brain communication. The authors sought to evaluate whether antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut–brain axis disruption in common marmosets of both sexes. For the first time in an NHP model, this study demonstrated that antibiotics induce gut dysbiosis, alter gut metabolites relevant to gut–brain communication, affect neuroendocrine responses in response to stressful stimuli, and change social behavior. Supported by ORIP (K01OD030514), NCI, and NIGMS.
Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates
Burdo et al., Gene Therapy. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11090835/
Nonhuman primates have served as a valuable resource for evaluating novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed. Together, these findings support the continued development of HIV eradicative cure strategies using CRISPR technology in humans. Supported by ORIP (P40OD012217, U42OD021458).