Selected Grantee Publications
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- nei
- nidcr
- Infectious Diseases
Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Tisoncik-Go et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49524-2
Maternal infection during pregnancy can have severe consequences on fetal development and survival. Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. This study suggests that reduced myelin resulting from Zika infection in utero is likely a contributing factor to severe deficits in brain development and microcephaly. Supported by ORIP (P51OD010425), NEI, and NIAID.
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.
Antiretroviral Therapy Reveals Triphasic Decay of Intact SIV Genomes and Persistence of Ancestral Variants
Fray et al., Cell Host & Microbe. 2023.
https://doi.org/10.1016/j.chom.2023.01.016
Antiretroviral therapy (ART) halts HIV-1 replication but is not curative; a pool of latently infected CD4+ T cells persists, and viremia rapidly rebounds if ART is stopped. Using an intact proviral DNA assay, researchers characterized quantitative and qualitative changes in CD4+ T cells for 4 years following ART initiation in rhesus macaques of both sexes. They found that viruses replicating at ART initiation had mutations conferring antibody escape, and sequences with large numbers of antibody escape mutations became less abundant at later time points. Together, these findings reveal that the population of simian immunodeficiency virus (SIV)–infected CD4+ T cells is dynamic and provide a framework for evaluating and interpreting intervention trials. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
The Latent Reservoir of Inducible, Infectious HIV-1 Does Not Decrease Despite Decades of Antiretroviral Therapy
McMyn et al., The Journal of Clinical Investigation. 2023.
https://www.doi.org/10.1172/JCI171554
Antiretroviral therapy (ART) does not eliminate the latent HIV reservoir, but it is unknown whether sustained reservoir decay occurs with long-term ART. Researchers used a quantitative viral outgrowth assay, an intact proviral DNA assay, and proviral sequencing to characterize the latent reservoir in men and women with HIV who had maintained suppression of viral replication on ART for 14 to 27 years. They found that the reservoir decay did not continue with long-term ART. Further studies could provide insight into the mechanism underlying these findings. These results reinforce the need for lifelong ART and indicate that the reservoir remains a major barrier to an HIV-1 cure. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
A Clade C HIV-1 Vaccine Protects Against Heterologous SHIV Infection by Modulating IgG Glycosylation and T Helper Response in Macaques
Sahoo et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abl4102
Vaccines for HIV-1 capable of generating a broadly cross-reactive neutralizing antibody response are needed urgently. The researchers tested the protective efficacy of a clade C HIV-1 vaccination regimen in male rhesus macaques. The vaccine was administered either orally using a needle-free injector or via parenteral injection. Significant protection was observed for both vaccination routes following the simian–human immunodeficiency virus (SHIV) challenge, with an estimated efficacy of 68% per exposure. The glycosylation profile of IgG and HIV-resistant helper T cell response contributes to the protection. Supported by ORIP (P51OD011132), NIAID, and NIDCR.
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.
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.
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.
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.