Selected Grantee Publications
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- Nonhuman Primate Models
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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.
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.
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.
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.
Inflammatory Blockade Prevents Injury to the Developing Pulmonary Gas Exchange Surface in Preterm Primates
Toth et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abl8574
Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25% to 40% of preterm births. Investigators used a prenatal rhesus macaque model to assess how fetal inflammation could affect lung development. They found that inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure. Blockade of the inflammatory cytokines IL-1β and TNFα ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells. These data provide new insight into key mechanisms of developmental lung injury and highlight targeted inflammatory blockade as a potential therapeutic approach to ameliorate lung injury in the neonatal population. Supported by ORIP (P51OD011107), NIAID, NHLBI, NICHD, and NIEHS.
Presence of Natural Killer B Cells in Simian Immunodeficiency Virus–Infected Colon That Have Properties and Functions Similar to Those of Natural Killer Cells and B Cells but Are a Distinct Cell Population
Cogswell et al., mSphere. 2022.
https://www.doi.org/10.1128/jvi.00235-22
HIV infection of the gut is associated with increased mucosal inflammation, and the role of natural killer B (NKB) cells in this process requires further investigation. In this study, the researchers used rhesus and cynomolgus macaque models to characterize the function and characteristics of NKB cells in response to simian immunodeficiency virus (SIV) infection. They reported that NKB cells can kill target cells, proliferate, and express several inflammatory cytokines. The properties of NKB cells could provide insight into the inflammation observed in the gut during SIV infection, and the individual contributions of each cytokine and receptor–ligand interaction could be explored in a future study. Supported by ORIP (P51OD011106), NIAID, and NIGMS.
Phagocytosis by an HIV Antibody Is Associated with Reduced Viremia Irrespective of Enhanced Complement Lysis
Spencer et al., Nature Communications. 2022.
https://doi.org/10.1038/s41467-022-28250-7
Researchers used the bNAb 10E8v4 targeting the HIV Env protein to examine the role of antibody-mediated effector and complement (C′) activity when 10E8v4 was administered prophylactically to rhesus monkeys challenged with simian-human immunodeficiency virus (SHIV). With sub-protective dosing, the researchers found a 78–88% reduction in post-acute viremia that was associated with 10E8v4–mediated phagocytosis. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to therapeutic efficacy against SHIV, while C′ functions do not contribute to efficacy in this context. This research informs the design of bNAb modifications for improving the protective efficacy of this therapeutic approach against HIV. Supported by ORIP (P51OD011092, U42OD023038) and NIAID.
Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection
Curtis et al., mSphere. 2022.
https://www.doi.org/10.1128/msphere.00839-21
A tailored, effective HIV vaccine is needed to prevent mother-to-child viral transmission. In nonhuman primate models, infection with simian–human immunodeficiency virus (SHIV) can be prevented by administering broadly neutralizing HIV envelope (Env)–specific antibodies. Investigators tested the efficacy of an intramuscular vaccine regimen against SHIV infection in male and female infant rhesus macaques. The vaccine induced Env-specific antibodies in plasma, with antibody-dependent cellular cytotoxicity and phagocytic function. These antibodies, however, were insufficient for protection against infection. Future studies could focus on improving the breadth of antibody response and improving cell-mediated immunity. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.