Selected Grantee Publications
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- 35 results found
- Immunology
- P40
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
SHIV Remission in Macaques With Early Treatment Initiation and Ultra Long-Lasting Antiviral Activity
Daly et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39632836
Antiretroviral therapy (ART) suppresses HIV and simian immunodeficiency virus (SIV) replication but cannot eliminate reservoirs of long-lived infected cells that enable rebound after discontinuation of ART. These researchers hypothesized that ART designed to have long-lasting activity and penetrate tissue reservoirs would be optimized against HIV or SIV remission. Macaques were treated with a four-drug regimen (i.e., oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine) designed to improve dosing of immune cells, with or without the immune-activating drug vesatolimod (VES), after the onset of SIV viremia. The animals were monitored for 1 year with treatment and 2 additional years following treatment discontinuation. Durable viral suppression was observed in all animals treated with the optimized ART regimen with or without VES. These results will inform novel HIV treatment regimens with long-lasting antiviral activity in humans. Supported by ORIP (P40OD028116).
Characterization of Collaborative Cross Mouse Founder Strain CAST/EiJ as a Novel Model for Lethal COVID-19
Baker et al., Scientific Reports. 2024.
https://www.nature.com/articles/s41598-024-77087-1
Researchers characterized the Collaborative Cross (CC) mouse model founder strain CAST/EiJ as a novel model for severe COVID-19, exhibiting high viral loads and mortality. By leveraging genetically diverse CC strains, this study identified variations in susceptibility and survival against SARS-CoV-2 variants. CAST/EiJ mice developed lung pathology and mortality despite antiviral defenses, making them a valuable tool for understanding host–pathogen interactions. The findings emphasize the utility of diverse animal models in uncovering genetic and immunological factors that influence disease outcomes, facilitating the development of targeted therapies against COVID-19 to mitigate future pandemics. Supported by ORIP (P40OD011102).
Administration of Anti-HIV-1 Broadly Neutralizing Monoclonal Antibodies With Increased Affinity to Fcγ Receptors During Acute SHIV AD8-EO Infection
Dias et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-51848-y
Anti-HIV broadly neutralizing antibodies (bNAbs) mediate virus neutralization and antiviral effector functions through Fab and Fc domains, respectively. This study investigated the efficacy of wild-type (WT) bNAbs and modified bNAbs with enhanced affinity for Fcγ receptors (S239D/I332E/A330L [DEL]) after acute simian-HIVAD8-EO (SHIVAD8-EO) infection in male and female rhesus macaques. The emergence of the virus in the plasma and lymph nodes occurred earlier in macaques given DEL bNAbs than in those given WT bNAbs. Overall, the administration of DEL bNAbs revealed higher levels of immune responses. The results suggest that bNAbs with an enhanced Fcγ receptor affinity offer a potential therapeutic strategy by targeting HIV more effectively during early infection stages. Supported by ORIP (P40OD028116), NCI, and NIAID.
Comparison of the Immunogenicity of mRNA-Encoded and Protein HIV-1 Env-ferritin Nanoparticle Designs
Mu et al., Journal of Virology. 2024.
https://journals.asm.org/doi/10.1128/jvi.00137-24
Inducing broadly neutralizing antibodies (bNAbs) against HIV-1 remains a challenge because of immune system limitations. This study compared the immunogenicity of mRNA-encoded membrane-bound envelope (Env) gp160 to HIV-1 Env-ferritin nanoparticle (NP) technology in inducing anti-HIV-1 bNAbs. Membrane-bound mRNA encoding gp160 was more immunogenic than the Env-ferritin NP design in DH270 UCA KI mice, but at lower doses. These results suggest further analysis of mRNA design expression and low-dose immunogenicity studies are necessary for anti-HIV-1 bNAbs. Supported by ORIP (P40OD012217, U42OD021458) 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).
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.
Pigs in Transplantation Research and Their Potential as Sources of Organs in Clinical Xenotransplantation
Raza et al., Comparative Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38359908/
The pig has now gained importance as a potential source of organs for clinical xenotransplantation. When an organ from a wild-type (i.e., genetically unmodified) pig is transplanted into an immunosuppressed nonhuman primate, a vigorous host immune response causes hyperacute rejection (within minutes or hours). This response has been largely overcome by (1) extensive gene editing of the organ-source pig and (2) administration to the recipient of novel immunosuppressive therapy based on blockade of the CD40/CD154 T-cell costimulation pathway. The combination of gene editing and novel immunosuppressive therapy has extended life-supporting pig kidney graft survival to greater than 1 year and of pig heart survival to up to 9 months. This review briefly describes the techniques of gene editing, the potential risks of transfer of porcine endogenous retroviruses with the organ, and the need for breeding and housing of donor pigs under biosecure conditions. Supported by ORIP (P40OD024628) 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.