Selected Grantee Publications
- Clear All
- 244 results found
- Microbiome
- Vaccines/Therapeutics
Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy Against HIV-1: A Phase 1 Clinical Trial
Julg et al., Nature Medicine. 2022.
https://www.doi.org/10.1038/s41591-022-01815-1
Previous evidence suggests that at least three broadly neutralizing antibodies (bNAbs) targeting different epitope regions are needed for robust treatment and control of HIV. The investigators evaluated the safety, tolerability, and pharmacokinetics of PGDM1400, an HIV-1 V2-glycan–specific antibody, in a first-in-human trial. The primary endpoints were safety, tolerability, pharmacokinetics, and antiviral activity. The trial met the prespecified endpoints in male and female adults. These data will help advance understanding of the capabilities, limitations, and future role of bNAb combinations in HIV prevention and care. Supported by ORIP (R01OD024917), NIAID, and NCATS.
Myeloid Cell Tropism Enables MHC-E–Restricted CD8+ T Cell Priming and Vaccine Efficacy by the RhCMV/SIV Vaccine
Hansen et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abn9301
Simian immunodeficiency virus (SIV) vaccines based on strain 68-1 rhesus cytomegalovirus vectors have been shown to arrest viral replication early in primary infection. The specific characteristics underlying this effect are not understood fully. In this study, the researchers used host microRNA–mediated vector tropism restriction to demonstrate that the targeted responses are dependent on vector infection of distinct cell types in a rhesus macaque model. Only vectors programmed to elicit major histocompatibility complex E–restricted CD8+ T cell responses provided protection against SIV challenge. These findings could be applied in the development of other vaccines for cancers and infectious diseases. Supported by ORIP (P51OD011092), 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.
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.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.
Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy
Zhang et al., Cancer Research. 2022.
https://pubmed.ncbi.nlm.nih.gov/34965933/
Antibody-peptide epitope conjugates (APEC) are a new class of modified antibody-drug conjugates that redirect T cell viral immunity against tumor cells. Investigators developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Based on functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus in ovarian cancer patients, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. The streamlined and systemic approach includes assessing APEC function in vivo using a new zebrafish xenograft platform that facilitates high-resolution single-cell imaging to assess therapy responses and then validating top candidates using traditional mouse xenograft studies and primary patient samples. This study develops a high-throughput preclinical platform to identify patient-specific antibody-peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma. Supported by ORIP (R24OD016761).