Selected Grantee Publications
Enhanced IL-17 Producing and Maintained Cytolytic Effector Functions of Gut Mucosal CD161+ CD8+ T Cells in SIV-Infected Rhesus Macaques
Thirugnanam et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535321/
HIV infection is associated with the depletion of CD161-expressing CD4+ Th17 cells, but the effects on other IL-17–producing T cell subsets are not understood fully. Researchers characterized the functions of non-invariant CD161-expressing CD8+ T cell subpopulations in peripheral blood and mucosal tissues of rhesus macaques (sex not specified) during chronic simian immunodeficiency virus (SIV) infection. They demonstrated that cell frequencies and function were unaffected by infection, but enhanced IL-17 production capacity and sustained Th1-type and cytolytic functions were observed. This work suggests that CD161-expressing CD8+ T cells might have important functions in gut mucosal immunity during chronic HIV infection. Supported by ORIP (P51OD011104, S10OD026800), NIAID, NIDDK, and NIMH.
Spontaneous HIV Expression During Suppressive ART Is Associated With the Magnitude and Function of HIV-Specific CD4+ and CD8+ T Cells
Dubé et al., Cell Host Microbe. 2023.
https://linkinghub.elsevier.com/retrieve/pii/S1931-3128(23)00331-1
CD4+ and CD8+ T cells are essential in the control of simian immunodeficiency virus and HIV infections, but the mechanisms are not understood fully. Using multiplexed single-cell RNAflow-fluorescence in situ hybridization, researchers quantified and phenotyped viral reservoirs spontaneously expressing viral RNA and the p24 protein in primary clinical samples from men. They reported associations between active reservoirs and HIV-specific CD4+ and CD8+ T cells, and the active reservoirs were largely dominated by defective proviruses. Their findings suggest that viral reservoirs maintain HIV-specific responses during suppressive antiretroviral therapy (ART), and low-level viral gene expression by spontaneous reservoirs is sufficient to maintain anti-HIV adaptive immunity. Supported by ORIP (P51OD011092) and NIAID.
CD8+ Cells and Small Viral Reservoirs Facilitate Post-ART Control of SIV Replication in M3+ Mauritian Cynomolgus Macaques Initiated on ART Two Weeks Post-Infection
Harwood et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10553806/
A rare group of people infected with HIV can achieve sustainable HIV remission after antiretroviral therapy (ART) withdrawal, but the underlying mechanisms are not understood fully. A team of investigators observed post-treatment control in a cohort of male cynomolgus macaques that were initiated on ART 2 weeks post-infection. Additionally, they reported that the cynomolgus macaques had smaller acute reservoirs than similarly infected rhesus macaques. Collectively, these data suggest that a combination of small reservoirs and immune-mediated virus suppression contributes to post-treatment control in cynomolgus macaques. This model could be used in future studies to develop therapeutic interventions. Supported by ORIP (P51OD011106, P40OD028116), NIAID, and NCI.
The Latent Reservoir of Inducible, Infectious HIV-1 Does Not Decrease Despite Decades of Antiretroviral Therapy
McMyn et al., The Journal of Clinical Investigation. 2023.
https://www.doi.org/10.1172/JCI171554
Antiretroviral therapy (ART) does not eliminate the latent HIV reservoir, but it is unknown whether sustained reservoir decay occurs with long-term ART. Researchers used a quantitative viral outgrowth assay, an intact proviral DNA assay, and proviral sequencing to characterize the latent reservoir in men and women with HIV who had maintained suppression of viral replication on ART for 14 to 27 years. They found that the reservoir decay did not continue with long-term ART. Further studies could provide insight into the mechanism underlying these findings. These results reinforce the need for lifelong ART and indicate that the reservoir remains a major barrier to an HIV-1 cure. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge With Simian-Tropic HIV
Swanstrom et al., eBioMedicine. 2023.
https://doi.org/10.1016/j.ebiom.2023.104764
Pre-exposure prophylaxis (PrEP) is effective in preventing new HIV infections, but regimen adherence remains a challenge. Antiretrovirals with long-acting pharmacokinetic properties could help overcome this limitation. Researchers examined the protective efficacy of lenacapavir, a first-in-class HIV capsid inhibitor, using male pigtail macaques. They reported that a single administration of the drug provided protection from simian-tropic HIV infection. These data demonstrate the value of this nonhuman primate model and support the clinical development of long-acting lenacapavir for PrEP in humans. Future studies could further explore and refine the drug exposure–efficacy relationship. Supported by ORIP (P40OD028116), NIAID, and NCI.
Downregulation of CCR5 on Brain Perivascular Macrophages in Simian Immunodeficiency Virus–Infected Rhesus Macaques
Bollimpelli et al., Nature Communications. 2023.
https://www.doi.org/10.1038/s41467-023-40430-7
Researchers have been exploring multiple strategies to develop an HIV vaccine. In this study, the investigators determined the immunogenicity and efficacy of intradermal and intramuscular routes of modified vaccinia Ankara (MVA) vaccination in female rhesus macaques. They found that both routes of MVA vaccination enabled control of viral replication, but only the intradermal vaccination was effective in protection against viral acquisition. Their findings suggest that the intradermal MVA vaccinations provide protection by modulating the innate and T helper responses. Taken together, this work underscores the importance of testing the influence of the route of immunization for HIV vaccines in humans. Supported by ORIP (P51OD011132, R24OD010976) and NIAID.
Antiretroviral Therapy Ameliorates Simian Immunodeficiency Virus–Associated Myocardial Inflammation by Dampening Interferon Signaling and Pathogen Response in the Heart
Robinson et al., The Journal of Infectious Diseases. 2023.
https://doi.org/10.1093/infdis/jiad105
HIV is associated with increased risk of cardiovascular disease, but the underlying mechanisms are not fully understood. Using RNA sequencing, investigators characterized the effects of simian immunodeficiency virus (SIV) infection on the hearts of male rhesus macaques. They demonstrated that SIV infection drives a canonical antiviral response in the heart, as well as dysregulation of genes involved in fatty acid shuttling and metabolism. Their findings suggest that antiretroviral therapy helps mitigate immune activation during viremic conditions and plays a cardioprotective role. Future studies are needed to assess the long-term effects of these dynamics. Supported by ORIP (P51OD011104), NIAID, NIMH, and NINDS.
A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection
Wahl et al., Nature Biotechnology. 2023.
https://www.nature.com/articles/s41587-023-01906-5
Germ-free (GF) mice are of limited value in the study of human-specific pathogens because they do not support their replication. In this report, investigators developed a GF humanized mouse model using the bone marrow–liver–thymus platform to provide a robust and flexible in vivo model that can be used to study the role of resident microbiota in human health and disease. They demonstrated that resident microbiota promote viral acquisition and pathogenesis by using two human-specific pathogens, Epstein–Barr virus and HIV. Supported by ORIP (P40OD010995), FIC, NIAID, NCI, and NIDDK.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Allogeneic Immunity Clears Latent Virus Following Allogeneic Stem Cell Transplantation in SIV-Infected ART-Suppressed Macaques
Wu et al., Immunity. 2023.
https://doi.org/10.1016/j.immuni.2023.04.019
Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been documented as curative for HIV, but the mechanisms are not yet known. Using Mauritian cynomolgus macaques of both sexes, researchers performed reduced-intensity alloHSCT experiments to define the individual contributions of allogeneic immunity and CCR5 deficiency to an alloHSCT-mediated HIV cure. They reported that allogeneic immunity was the major driver of reservoir clearance, mediating graft-versus-reservoir effects in HIV infection. Their results also point to a protective mechanism for CCR5 deficiency early during engraftment. Future efforts could focus on harnessing the beneficial effects of allogeneic immunity while avoiding graft-versus-host disease. Supported by ORIP (P51OD011092) and NIAID.