Selected Grantee Publications
- Clear All
- 10 results found
- Nonhuman Primate Models
- Genetics
- 2023
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.
Antiretroviral Therapy Reveals Triphasic Decay of Intact SIV Genomes and Persistence of Ancestral Variants
Fray et al., Cell Host & Microbe. 2023.
https://doi.org/10.1016/j.chom.2023.01.016
Antiretroviral therapy (ART) halts HIV-1 replication but is not curative; a pool of latently infected CD4+ T cells persists, and viremia rapidly rebounds if ART is stopped. Using an intact proviral DNA assay, researchers characterized quantitative and qualitative changes in CD4+ T cells for 4 years following ART initiation in rhesus macaques of both sexes. They found that viruses replicating at ART initiation had mutations conferring antibody escape, and sequences with large numbers of antibody escape mutations became less abundant at later time points. Together, these findings reveal that the population of simian immunodeficiency virus (SIV)–infected CD4+ T cells is dynamic and provide a framework for evaluating and interpreting intervention trials. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
AZD5582 Plus SIV-Specific Antibodies Reduce Lymph Node Viral Reservoirs in Antiretroviral Therapy–Suppressed Macaques
Dashti et al., Nature Medicine. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579098/
Researchers are interested in targeting the HIV reservoir via a latency reversal and clearance approach. Previously, investigators demonstrated that AZD5582 induces systemic latency reversal in rhesus macaques and humanized mice, but a consistent reduction in the viral reservoir was not observed. In the current study, they combined AZD5582 with four simian immunodeficiency virus (SIV)–specific rhesus monoclonal antibodies using rhesus macaques of both sexes. They reported a reduction in total and replication-competent SIV DNA in lymph node–derived CD4+ T cells in the treated macaques. These findings provide proof of concept for the potential of the latency reversal and clearance HIV cure strategy. Supported by ORIP (P51OD011132, R01OD011095), NIAID, NCI, and NHLBI.
Biphasic Decay of Intact SHIV Genomes Following Initiation of Antiretroviral Therapy Complicates Analysis of Interventions Targeting the Reservoir
Kumar et al., PNAS. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/
The latent HIV-1 reservoir persists with antiretroviral therapy (ART), and assays for quantifying intact proviruses in nonhuman primate models are needed. Researchers used a simian–human immunodeficiency virus (SHIV) intact proviral DNA assay to describe viral decay during the first year of ART in female rhesus macaques. Their results suggest that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase and a slower second phase. These findings can provide insight for future studies using SHIV models, as well as new cure interventions. Supported by ORIP (R01OD011095) 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.
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.
A Live Dengue Virus Vaccine Carrying a Chimeric Envelope Glycoprotein Elicits Dual DENV2–DENV4 Serotype-Specific Immunity
Young et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/36914616/
Dengue vaccine development is challenging because some virus-specific antibodies are protective, whereas others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to induce balanced protective immunity. To simplify live-virus vaccine design, investigators identified co-evolutionary constraints inherent in flavivirus virion assembly. They found that the chimeric virus replicated efficiently in vitro and in vivo and that a single inoculation induced type-specific neutralizing antibodies in male macaques. These findings can be applied to the development of bivalent live dengue vaccines that induce independent immunity to multiple serotypes. Supported by ORIP (P40OD012217) 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.