Selected Grantee Publications
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- Vaccines/Therapeutics
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
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.
Lymphoid Tissues Contribute to Plasma Viral Clonotypes Early After Antiretroviral Therapy Interruption in SIV-Infected Rhesus Macaques
Solis-Leal et al., Science Translational Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/38091409/
Researchers are interested in better understanding the sources, timing, and mechanisms of HIV rebound that occurs after interruption of antiretroviral therapy (ART). Using rhesus macaques (sex not specified), investigators tracked barcoded simian immunodeficiency virus (SIV) clonotypes over time and among tissues. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. Additionally, the authors reported that CD4+ T cells harbored the most viral RNA after ART interruption. These tissues are likely to contribute to viral reactivation and rebound after ART interruption, but further studies are needed to evaluate the relative potential contributions from other tissues and organs. Supported by ORIP (P51OD011104, P51OD011133, S10OD028732, S10OD028653), NCI, NIMH, and NINDS.
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons et al., c. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674359/
Current HIV treatment strategies are focused on forced proviral reactivation and elimination of reactivated cells with immunological or toxin-based technologies. Researchers have proposed the use of a novel “block-lock-stop” approach, which entails the long-term durable silencing of viral expression and permanent transcriptional deactivation of the latent provirus. In the present study, the authors present this approach and its rationale. More research is needed to understand the (1) epigenetic architecture of integrated provirus, (2) cell types and epigenetic cell states that favor viral rebound, (3) molecular functions of Tat (a protein that controls transcription of HIV) and host factors that prevent permanent silencing, (4) human endogenous retrovirus silencing in the genome, and (5) approaches to generate defective proviruses. Additionally, community engagement is crucial for this effort. Supported by ORIP (K01OD031900), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS.
Timing of Initiation of Anti-Retroviral Therapy Predicts Post-Treatment Control of SIV Replication
Pinkevych et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558076/
Researchers are interested in approaches to reducing viral rebound following interruption of antiretroviral therapy, but more work is needed to understand major factors that determine the viral “setpoint” level. Researchers previously assessed how timing of treatment can affect the frequency of rebound from latency. In the current study, the authors analyzed data from multiple studies of simian immunodeficiency virus (SIV) infection in rhesus macaques to further explore the dynamics and predictors of post-treatment viral control. They determined that the timing of treatment initiation was a major predictor of both the level and the duration of post-rebound SIV control. These findings could help inform future treatments. Supported by ORIP (U42OD011023, P51OD011132, P51OD011092), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS
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.
Osteopontin Is an Integral Mediator of Cardiac Interstitial Fibrosis in Models of Human Immunodeficiency Virus Infection
Robinson et al., The Journal of Infectious Diseases. 2023.
https://www.doi.org/10.1093/infdis/jiad149
HIV infection is associated with increased risk of cardiovascular disease. Plasma osteopontin (Opn) is correlated with cardiac pathology, but more work is needed to understand the underlying mechanisms driving cardiac fibrosis. Researchers explored this topic using mouse embryonic fibroblasts, male macaques, and humanized mice of both sexes. They reported the accumulation of Opn in the heart with simian immunodeficiency virus infection. Systemic inhibition of Opn can prevent HIV-associated interstitial fibrosis in the left ventricle. These findings suggest that Opn could be a potential target for adjunctive therapies to reduce cardiac fibrosis in people with HIV. Supported by ORIP (P51OD011104), NIAID, NHLBI, NIMH, and NINDS.
Brain Microglia Serve as a Persistent HIV Reservoir Despite Durable Antiretroviral Therapy
Tang et al., The Journal of Clinical Investigation. 2023.
https://www.doi.org/10.1172/JCI167417
Brain microglia are likely to play a role in rebound viremia following the cessation of antiretroviral therapy, but more work is needed to fully understand HIV persistence in the central nervous system (CNS). The investigators developed a protocol to isolate highly pure populations of brain myeloid cells and microglia from the tissues of male rhesus macaques, as well as from rapid autopsies of men and women with HIV. Their observations support the concept that brain microglia are a stable reservoir of quiescent infection. Thus, this work provides a physiologically relevant platform for studies of the biology of CNS reservoirs. Supported by ORIP (P51OD011132), NIAID, and NIMH.
Longitudinal Characterization of Circulating Extracellular Vesicles and Small RNA During Simian Immunodeficiency Virus Infection and Antiretroviral Therapy
Huang et al., AIDS. 2023.
https://www.doi.org/10.1097/QAD.0000000000003487
Antiretroviral therapy is effective for controlling HIV infection but does not fully prevent early aging disorders or serious non-AIDS events among people with HIV. Using pigtail and rhesus macaques (sex not specified), researchers profiled extracellular vesicle small RNAs during different phases of simian immunodeficiency virus infection to explore the potential relationship between extracellular vesicle–associated small RNAs and the infection process. They reported that average particle counts correlated with infection, but the trend could not be explained fully by virions. These findings raise new questions about the distribution of extracellular vesicle RNAs in HIV latent infection. Supported by ORIP (U42OD013117), NIDA, NIMH, NIAID, NCI, and NINDS.
Chronic Immune Activation and Gut Barrier Dysfunction Is Associated with Neuroinflammation in ART-Suppressed SIV+ Rhesus Macaques
Byrnes et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10085024/
About 40% of people with HIV develop neurocognitive disorders, potentially resulting from persistent infection in the brain and neuroinflammation. Investigators characterized the central nervous system reservoir and immune environment of simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes during acute, chronic, or antiretroviral therapy (ART)–suppressed infection. They reported that neuroinflammation and blood–brain barrier dysfunction correlated with viremia and immune activation in the gut. Their findings suggest that gastrointestinal tract damage can contribute to neuroimmune activation and inflammation, even in the absence of SIV or HIV infection. This work also has implications for other neurological disorders where chronic inflammation is associated with pathogenesis. Supported by ORIP (P51OD011132, P51OD011092, U42OD011023, R24OD010445), NIAID, NCI, and NIMH.