Selected Grantee Publications
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- Alzheimer's Disease
- Immunology
A Cellular Trafficking Signal in the SIV Envelope Protein Cytoplasmic Domain Is Strongly Selected for in Pathogenic Infection
Lawrence et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1010507
Envelope glycoproteins within the cytoplasmic domain of HIV and simian immunodeficiency virus (SIV) include a tyrosine-based motif that mediates endocytosis and polarized sorting in infected cells. Mutation of this tracking signal has been shown to lead to suppressed viral replication and failed systemic immune activation, but the mechanism has not been explored fully. Using rhesus and pigtail macaque models, the researchers demonstrated that molecular clones containing the mutations reconstitute signals for both endocytosis and polarized sorting. Their findings suggest strong selection pressure for these processes during pathogenic HIV and SIV infection. Supported by ORIP (P51OD011104), NCI, and NIAID.
Large Comparative Analyses of Primate Body Site Microbiomes Indicate That the Oral Microbiome Is Unique Among All Body Sites and Conserved Among Nonhuman Primates
Asangba et al., Microbiology Spectrum. 2022.
https://www.doi.org/10.1128/spectrum.01643-21
Microbiomes are critical to host health and disease, but large gaps remain in the understanding of the determinants, coevolution, and variation of microbiomes across body sites and host species. Thus, researchers conducted the largest comparative study of primate microbiomes to date by investigating microbiome community composition at eight distinct body sites in 17 host species. They found that the oral microbiome is unique in exhibiting notable similarity across primate species while being distinct from the microbiomes of all other body sites and host species. This finding suggests conserved oral microbial niche specialization, despite substantial dietary and phylogenetic differences among primates. Supported by ORIP (P51OD010425, P51OD011107, P40OD010965, R01OD010980), NIA, NIAID, and NICHD.
The Ex Vivo Pharmacology of HIV-1 Antiretrovirals Differs Between Macaques and Humans
Herrera et al., iScience. 2022.
https://www.doi.org/10.1016/j.isci.2022.104409
Nonhuman primates (NHPs) are used widely for studies of antiretroviral (ARV)–based pre‑exposure prophylaxis (PrEP), but more work is needed to address dose–efficacy discrepancies between NHP studies and human clinical trials of PrEP candidates. Investigators explored the use of colorectal and cervicovaginal ex vivo mucosal tissue explants as a bridging model between NHPs and humans. They reported differences in inhibitory potency of drug combinations between NHP and human mucosal tissue explants. These findings suggest that tissue explants can help researchers refine and interpret NHP ARV studies. Supported by ORIP (P51OD011104) and NIAID.
Cannabinoid Receptor 1 Antagonist Genistein Attenuates Marijuana-Induced Vascular Inflammation
Wei et al., Cell. 2022.
https://www.doi.org/10.1016/j.cell.2022.04.005
Marijuana use is increasing and is associated with increased risk of cardiovascular disease (CVD); however, the link between marijuana and CVD remains largely unknown. Investigators demonstrated that a psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9‑THC), activates cannabinoid receptor 1 (CB1), causing vascular inflammation, oxidative stress, endothelial dysfunction, and atherosclerosis. This in silico virtual screening study suggested that genistein, a soybean isoflavone, would be a putative CB1 antagonist. Their validation study showed that in male mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. This study for the first time revealed that genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis while preserving clinically useful effects. Supported by ORIP (S10OD030452) and others.
Altered Expression of ACE2 and Co-Receptors of SARS-CoV-2 in the Gut Mucosa of the SIV Model of HIV/AIDS
Hu et al., Frontiers in Microbiology. 2022.
https://www.doi.org/10.3389/fmicb.2022.879152
The investigators assessed the influence of pre-existing HIV infection—which is known to target the gut mucosal immune system—on the vulnerability to SARS-CoV-2 infection and disease. Using a rhesus macaque model (sex not specified), they investigated changes in the expression of ACE2 and other SARS-CoV-2 receptors and related pathways. Simian immunodeficiency virus (SIV) infection resulted in sustained or increased ACE2 expression in an inflamed and immune-impaired gut mucosal microenvironment. These changes are likely to increase susceptibility to SARS-CoV-2 infection and disease severity. Taken together, these results demonstrate the utility of SIV models to fill knowledge gaps related to HIV infection and coinfections. Supported by ORIP (P51OD011107) and NIAID.
Generation of SIV-Resistant T Cells and Macrophages from Nonhuman Primate Induced Pluripotent Stem Cells with Edited CCR5 Locus
D’Souza et al., Stem Cell Reports. 2022.
https://www.doi.org/10.1016/j.stemcr.2022.03.003
Genetically modified T cells have shown promise as a potential therapy for HIV. A renewable source of T cells from induced pluripotent stem cells (iPSCs) could help to further research progress in this area. The researchers used Mauritian cynomolgus macaques to generate simian immunodeficiency virus (SIV)–resistant T cells and macrophages from iPSCs. These engineered cells demonstrated impaired capacity for differentiation into CD4+CD8+ T cells. T cells and macrophages from the edited iPSCs did not support SIV replication. These findings could be applied to the development of new HIV therapies. Supported by ORIP (R24OD021322, P51OD011106) and NHLBI.
Adverse Biobehavioral Effects in Infants Resulting from Pregnant Rhesus Macaques’ Exposure to Wildfire Smoke
Capitanio et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-29436-9
Exposure to wildfire smoke (WFS) is a growing health concern as wildfires increase in number and size due to climate change. Researchers found that developing rhesus monkeys exposed to WFS from the Camp Fire in California (November 2018) during the first third of gestation exhibited greater inflammation, blunted cortisol, more passive behavior, and memory impairment compared to animals conceived after smoke had dissipated. Analysis of a historical control cohort did not support the alternative hypothesis that conception timing alone explained the results. These findings suggest that WFS may have a teratogenic effect on neural development in the primate fetus. Supported by ORIP (P51OD011107, R24OD010962) and NIEHS.
Antimicrobial Prophylaxis Does Not Improve Post-Surgical Outcomes in SIV/SHIV–Uninfected or SIV/SHIV–Infected Macaques (Macaca mulatta and Macaca fascicularis) Based on a Retrospective Analysis
Moats et al., PLOS One. 2022.
https://www.doi.org/10.1371/journal.pone.0266616
Some institutions routinely administer antimicrobial prophylaxis to nonhuman primates prior to surgery to prevent surgical site infections. In this study, the investigators assessed the influence of antimicrobial prophylaxis on complication rates in macaques of both sexes receiving peripheral lymph node (PLN) and laparoscopic biopsies. After PLN biopsies, no significant differences were observed between animals that received antimicrobial prophylaxis and those that did not. After laparoscopic biopsies, complication rates were greater in animals that received antimicrobial prophylaxis. Because of these findings, the authors recommend eliminating the use of unnecessary antibiotics in research animals. Supported by ORIP (U42OD023038, P51OD011092).
Early Post-Vaccination Gene Signatures Correlate With the Magnitude and Function of Vaccine-Induced HIV Envelope–Specific Plasma Antibodies in Infant Rhesus Macaques
Vijayan et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.840976
An effective vaccine is needed to reduce HIV infections, particularly among younger people. The initiation of an HIV vaccine regimen in early life could allow the development of mature HIV‑specific antibody responses that protect against infection. The investigators compared the effects of two vaccine regimens in infant rhesus macaques (sex not specified). Both vaccines induced a rapid innate response, indicated by elevated inflammatory plasma cytokines and altered gene expression. By performing a network analysis, the investigators identified differentially expressed genes associated with B cell activation. These findings suggest that vaccine-induced immunity can be optimized by modulating specific antibody and T cell responses. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
Obesity Alters Pathology and Treatment Response in Inflammatory Disease
Bapat et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-04536-0
Obesity and metabolic disease have been shown to affect immunotherapeutic outcomes. By studying classical type 2 T helper cells (TH2) in lean and obese male mouse models for atopic dermatitis, investigators found that the biologic therapies protected lean mice but exacerbated disease in obese mice. RNA sequencing and genome analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells in obese mice when compared to lean mice, indicating that PPARγ is required to prevent aberrant non-TH2 inflammation. Understanding the effects of obesity on immunological disease could inform a potential precision medicine approach to target obesity-induced immune dysregulation. Supported by ORIP (S10OD023689), NIAID, NCI, NIDDK, and NIGMS.