Selected Grantee Publications
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.
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.
Common and Divergent Features of T Cells From Blood, Gut, and Genital Tract of Antiretroviral Therapy–Treated HIV+ Women
Xie et al., Journal of Immunology. 2022.
https://www.doi.org/10.4049/jimmunol.2101102
T cells residing in mucosal tissues play important roles in homeostasis and defense against microbial pathogens, but how organ system environments affect the properties of resident T cells is relatively unknown. Researchers phenotyped T cells in the gut and reproductive tract using blood and tissue samples from women with HIV who have achieved viral suppression via antiretroviral therapy. The T cells exhibited differing expression of CD69 and CD103 markers, whereas resident memory CD8+ T cells from the female reproductive tract expressed PD1 preferentially. Additionally, CXCR4+ T inflammatory mucosal cells expressed multiple chemokine receptors differentially. These results suggest that T cells take on distinct properties in different mucosal sites, which allows them to tailor activities to their surrounding milieu. This study offers important insights for reproductive medicine in women. Supported by ORIP (S10OD018040), NHLBI, NIAID, and NIDDK.
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.
Complex Decay Dynamics of HIV Virions, Intact and Defective Proviruses, and 2LTR Circles Following Initiation of Antiretroviral Therapy
White et al., PNAS. 2022.
https://doi.org/10.1073/pnas.2120326119
In people living with HIV-1 (PLWH) who start antiretroviral therapy (ART), virus in blood decreases rapidly to below detection, but remaining infected cells may become part of the latent reservoir. Researchers investigated viral decay dynamics and identified decay processes with pronounced differences between intact and defective proviruses. Infected cells that survive second-phase decay may down-regulate HIV-1 gene expression and enter the stable latent reservoir. This research provides insight into meaningful latent reservoir markers and mechanisms for elimination of cells with intact viral genomes. Supported by ORIP (R01OD011095) 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.