Selected Grantee Publications
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- 179 results found
- HIV/AIDS
- Rare Diseases
Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques
Boby et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.835686
Recent studies suggest that people with HIV—particularly those not receiving antiretroviral therapy or those with low CD4 cell counts—are at increased risk of severe illness from SARS‑CoV-2 coinfection. Angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, is likely to play an important role in modulating physiological and pathological events during HIV infection. In this study, the researchers used a rhesus macaque model to characterize the expression profiles of ACE2, other renin-angiotensin system (RAS)–associated genes (AGTR1/2, ADAM17, and TMPRSS2), and inflammatory cytokines (IL-1β, IL-6, and TNF‑α) in the jejunum and lung during simian immunodeficiency virus (SIV) infection. SIV infection was associated with multiple changes in gene expression, including downregulation of ACE2, which could lead to loss of gut homeostasis. Further studies could provide insight on the role of RAS-associated proteins during HIV and SARS-CoV-2 co-infection. Supported by ORIP (P51OD011104) and NIDDK.
Estimation of the In Vivo Neutralization Potency of eCD4Ig and Conditions for AAV-Mediated Production for SHIV Long-Term Remission
Goyal et al., Science Advances. 2022.
https://www.doi.org/10.1126/sciadv.abj5666
The engineered protein eCD4Ig, a synthetic antibody-like inhibitor designed to limit HIV entry into cells, shows promise as an approach to achieve HIV remission without antiretroviral therapy. Researchers used mathematical modeling to characterize in vivo antiviral neutralization of eCD4Ig, as well as possible antibody-dependent cell-mediated cytotoxicity effects, in rhesus macaques infected with simian–human immunodeficiency virus (SHIV) (sex not specified). The research team modeled SHIV and pharmacokinetics dynamics and projected the levels of eCD4Ig needed with a viral vector production approach to suppress SHIV viremia. The data suggest that endogenous, continuous expression of eCD4Ig could overcome the diminishing effects of antidrug antibodies and allow long-term remission of SHIV viremia in nonhuman primates. Supported by ORIP (P51OD011132) and NIAID.
Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy
Solis-Leal et al., Viruses. 2022.
https://www.doi.org/10.3390/v14010139
The central nervous system (CNS) HIV reservoir contributes to residual neuroimmune activation, which can lead to HIV-associated neurocognitive disorder. Researchers characterized the expression of signaling molecules associated with inflammation in plasma, cerebrospinal fluid, and basal ganglia of Chinese-origin rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV). They reported a correlation between levels of CCL2 in plasma and cerebrospinal fluid, suggesting that researchers could infer the degree of CNS inflammation by testing CCL2 levels in peripheral blood. Overall, these findings provide insight into neuroinflammation and signaling associated with HIV persistence in the CNS. Supported by ORIP (P51OD011104, P51OD011133), NIMH, and NINDS.
Cannabinoid Control of Gingival Immune Activation in Chronically SIV-Infected Rhesus Macaques Involves Modulation of the Indoleamine-2,3-Dioxygenase-1 Pathway and Salivary Microbiome
McDew-White et al., EBioMedicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34954656/
HIV-associated periodontal disease (PD) affects people living with HIV (PLWH) on combination anti-retroviral therapy (cART). Researchers used a systems biology approach to investigate the molecular, metabolome, and microbiome changes underlying PD and its modulation by phytocannabinoids (Δ9-THC) in rhesus macaques. Δ9-THC reduced IDO1 protein expression. The findings suggest that phytocannabinoids may help reduce gingival/systemic inflammation, salivary dysbiosis, and potentially metabolic disease in PLWH on cART. Supported by ORIP (P51OD011104, P51OD011133, U42OD010442), NIAID, NIDA, NIDDK, NIDCR, and NIMH.
Dynamics and Origin of Rebound Viremia in SHIV-Infected Infant Macaques Following Interruption of Long-Term ART
Obregon-Perko et al., JCI Insight. 2021.
https://pubmed.ncbi.nlm.nih.gov/34699383/
Animal models that recapitulate human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics, mechanisms of disease, and testing of vaccines and therapeutics. A group of male pigtail macaques (PTMs) were euthanized either 6- or 21-days after SARS-CoV-2 viral challenge and demonstrated mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, virus-targeting T cells were predominantly CD4+, increases in circulating inflammatory and coagulation markers, pulmonary pathologic lesions, and the development of neutralizing antibodies were observed. Collectively, the data suggests PTMs are a valuable model to study COVID-19 pathogenesis and may be useful for testing vaccines and therapeutics. Supported by ORIP (P51OD011104) and NIAID.
Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation in a Tuberculosis/Simian Immunodeficiency Virus Coinfection Model
Sharan et al., Journal of Clinical Investigation. 2021.
https://pubmed.ncbi.nlm.nih.gov/34855621/
In the rhesus macaque model for Mycobacterium tuberculosis plus simian immunodeficiency virus (SIV) co-infection, chronic immune activation rather than depletion of CD4+ T cells correlates with reactivation of latent tuberculosis infection (LTBI). Researchers administered combined antiretroviral therapy (cART) at 2 weeks post-SIV co-infection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival led to better control of viral replication and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. Supported by ORIP (K01OD031898, P51OD011133, P51OD011132, S10OD028653) and NIAID.
Deciphering the Role of Mucosal Immune Responses and the Cervicovaginal Microbiome in Resistance to HIV Infection in HIV-Exposed Seronegative Women
Ponnan et al., Microbiology Spectrum. 2021.
https://journals.asm.org/doi/10.1128/Spectrum.00470-21
Identifying correlates of protection in HIV-exposed seronegative (HESN) individuals requires identification of HIV-specific local immune responses. Researchers performed a comprehensive investigation of the vaginal mucosa and cervicovaginal microbiome in HESN women. They found elevated antiviral cytokines, soluble immunoglobulins, activated NK cells, CXCR5+ CD8+ T cells, and T follicular helper cells in HESN women compared to HIV-unexposed healthy women. They also found greater bacterial diversity and increased abundance of Gardnerella species in the mucosa of HESN women. These findings suggest that the genital tract of HESN women contains innate immune factors, antiviral mediators, and T cell subsets that protect against HIV. Supported by ORIP (P51OD011132) and NIAID.
CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques
Sarkar et al., Frontiers in Immunology. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.757811/full
Researchers investigated the humoral response in vaccinated rhesus macaques with CD4+ T cell depletion, using the VC10014 DNA protein co-immunization vaccine platform (with gp160 plasmids and gp140 trimeric proteins derived from an HIV-1 infected subject). Both CD4+-depleted and non-depleted animals developed comparable Tier 1 and 2 heterologous HIV-1 neutralizing plasma antibody titers. Thus, primates generate HIV neutralizing antibodies in the absence of robust CD4+ T cell help, which has important implications for vaccine development. Supported by ORIP (P51OD011092, P40OD028116, U42OD023038, U42OD010426), NIAID, and NIDCR.
Safety, Pharmacokinetics and Antiviral Activity of PGT121, a Broadly Neutralizing Monoclonal Antibody Against HIV-1: A Randomized, Placebo-Controlled, Phase 1 Clinical Trial
Stephenson et al., Nature Medicine. 2021.
https://doi.org/10.1038/s41591-021-01509-0
Researchers carried out a double-blind trial of one administration of the HIV-1 V3-glycan-specific antibody (Ab) PGT121 in HIV-uninfected and HIV-infected adults on antiretroviral therapy (ART), as well as an open-label trial of one infusion of PGT121 in viremic HIV-infected adults not on ART. The investigators observed no treatment-related serious adverse events among the 48 participants, and neutralizing anti-drug Abs were not elicited. PGT121 reduced plasma HIV RNA by a median of 1.77 log in viremic participants. Two individuals experienced ART-free viral suppression for ≥168 days following Ab infusion. These findings motivate further investigation of Ab-based therapeutic strategies for long-term HIV suppression. Supported by ORIP (R01OD024917, R01OD011095), NIAID, and NCATS.
A Novel Non-Human Primate Model of Pelizaeus-Merzbacher Disease
Sherman et al., Neurobiology of Disease. 2021.
https://www.sciencedirect.com/science/article/pii/S096999612100214X
Pelizaeus-Merzbacher disease (PMD) in humans is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Investigators report on three spontaneous cases of male neonatal rhesus macaques (RMs) with clinical symptoms of hypomyelinating disease. Genetic analysis revealed that the parents of these related RMs carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These RMs represent the first reported NHP model of PMD, providing an opportunity for studies to promote myelination in pediatric hypomyelinating diseases, as other animal models for PMD do not fully mimic the human disorder. Supported by ORIP (R24OD021324, P51OD011092, and S10OD025002) and NINDS.