Selected Grantee Publications
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.
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.
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.
The Landscape of Tolerated Genetic Variation in Humans and Primates
Gao et al., Science. 2023.
Investigators created a whole-genome sequence database from 809 nonhuman primates (NHPs) of 233 species to test the hypothesis that gene variants that do not cause disease in NHPs would likely be benign also in humans. They found that 99% of the genetic variants that were benign in NHPs also were classified as benign in the human ClinVar database. In contrast, only 71% to 87% of genomic variants classified as benign in non-primate animals were benign in humans. Building on this approach, the authors reclassified more than 4 million human genetic variants of unknown health impact as likely being benign based on effects in NHPs. This work illustrates the power of comparative medicine approaches between NHPs and humans. Supported by ORIP (P40OD024628, P51OD011106) and NIGMS.
In-Depth Virological and Immunological Characterization of HIV-1 Cure after CCR5A32/A32 Allogeneic Hematopoietic Stem Cell Transplantation
Jensen et al., Nature Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/36807684/
Evidence suggests that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure HIV-1, but the immunological and virological correlates are unknown. Investigators performed a longitudinal virological and immunological analysis of the peripheral blood and tissue compartments of a 53-year-old male patient more than 9 years after CCR5Δ32/Δ32 allogeneic HSCT and 48 months after analytical treatment interruption. Sporadic traces of HIV-1 DNA were detected in peripheral T cell subsets and tissue-derived samples, but repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice of both sexes did not reveal replication-competent virus. This case provides new insights that could guide future cure strategies. Supported by ORIP (P51OD011092) and NIAID.
SIV Infection Regulates Compartmentalization of Circulating Blood Plasma miRNAs within Extracellular Vesicles (EVs) and Extracellular Condensates (ECs) and Decreases EV-Associated miRNA-128
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10059597/
MicroRNAs (miRNAs) are thought to be involved in HIV pathogenesis, but the effect of HIV on the compartmentalization of miRNAs within extracellular particles is unclear. Researchers sequenced the small RNA population of paired EVs and ECs from male rhesus macaques. They showed that extracellular miRNAs in blood plasma are not restricted to any type of extracellular particles but are associated with lipid‑based carriers, with a significant proportion associated with ECs. Further, simian immunodeficiency virus (SIV) infection altered the miRNAome profile of EVs and revealed miR‑128‑3p as a potential target of infection. This work suggests that EV‑ and EC‑associated miRNAs potentially could serve as biomarkers for various diseases. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.
Alterations in Abundance and Compartmentalization of miRNAs in Blood Plasma Extracellular Vesicles and Extracellular Condensates during HIV/SIV Infection and its Modulation by Antiretroviral Therapy (ART) and Delta-9-Tetrahydrocannabinol (Δ9-THC)
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053514/
MicroRNAs (miRNAs) have been shown to regulate host response to HIV infection. Previously, investigators proposed that the assortment of extracellular miRNAs into distinct carriers could provide a new dimension to miRNA-based biomarkers. In this follow-up study, the investigators used particle purification liquid chromatography to determine the abundance and compartmentalization of blood plasma extracellular miRNAs into extracellular vesicles and extracellular condensates during simian immunodeficiency virus (SIV) infection in male rhesus macaques. They reported that different treatments—combination ART and Δ9‑THC—impart distinct effects on the enrichment and compartmentalization of extracellular miRNAs. These data suggest that the extracellular miRNA profile in blood plasma is altered following SIV infection. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.