Selected Grantee Publications
- Clear All
- 234 results found
- Infectious Diseases
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.
IL-21-IgFc Immunotherapy Alters Transcriptional Landscape of Lymph Node Cells Leading to Enhanced Flu Vaccine Response in Aging and SIV Infection
Pallikkuth et al., Aging Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/37712598/
Aging is associated with increased risk of seasonal flu disease burden and serious flu-related complications, particularly for people with HIV. In this study, investigators aimed to elucidate the immunomodulation following flu vaccination in aging male and female rhesus macaques infected with simian immunodeficiency virus (SIV). Their results suggest that IL-21 treatment at the time of flu vaccination modulates the inductive lymph node germinal center activity to reverse SIV-associated immune dysfunction. The authors identified IL-21 as a potential candidate molecule for immunotherapy to enhance flu vaccine responses in affected populations. Further studies could examine the overall benefit of IL-21 immunotherapy on mucosal lung immunity and protection against infection. Supported by ORIP (R24OD010947), NIA, and NIAID.
Intradermal but Not Intramuscular Modified Vaccinia Ankara Immunizations Protect Against Intravaginal Tier2 Simian–Human Immunodeficiency Virus Challenges in Female Macaques
Bollimpelli et al., Nature Communications. 2023.
https://www.doi.org/10.1038/s41467-023-40430-7
Researchers have been exploring multiple strategies to develop an HIV vaccine. In this study, the investigators determined the immunogenicity and efficacy of intradermal and intramuscular routes of modified vaccinia Ankara (MVA) vaccination in female rhesus macaques. They found that both routes of MVA vaccination enabled control of viral replication, but only the intradermal vaccination was effective in protection against viral acquisition. Their findings suggest that the intradermal MVA vaccinations provide protection by modulating the innate and T helper responses. Taken together, this work underscores the importance of testing the influence of the route of immunization for HIV vaccines in humans. Supported by ORIP (P51OD011132, R24OD010976) and NIAID.
Host Immunity Associated With Spontaneous Suppression of Viremia in Therapy-Naïve Young Rhesus Macaques Following Neonatal SHIV Infection
Evangelous et al., Journal of Virology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688376/
Previously, investigators developed a pediatric rhesus macaque model for simian–human immunodeficiency virus infection that can be exploited to identify host immunity associated with viremia suppression. In the present study, they used the model (with male and female animals) to characterize humoral and cellular immunity and plasma biomarkers associated with spontaneous viremia suppression. They identified CD8-expressing cells and varied T-cell subsets that were associated with viremia suppression. Additionally, the authors observed intermediate monocytes with upregulation of inhibitory genes that previously had been reported only in cytotoxic cells. These findings suggest a complex immunologic milieu of viremia suppression in pediatric populations. Supported by ORIP (P51OD011092, U42OD010426) and NIAID.
Conjugation of HIV-1 Envelope to Hepatitis B Surface Antigen Alters Vaccine Responses in Rhesus Macaques
Nettere et al., NPJ Vaccines. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673864/
Researchers are interested in developing an HIV-1 vaccine that improves upon the regimen used in the RV144 clinical trial. The authors tested the hypothesis that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T-cell help and improve antibody production against HIV-1. Using juvenile rhesus macaques of both sexes, they evaluated the immunogenicity of their conjugate regimen. Their findings suggest that conjugate vaccination can engage both HIV-1 Env– and hepatitis B surface antigen–specific Tcell help and modify antibody responses at early time points. This work may help inform future efforts to improve the durability and efficacy of next-generation HIV vaccines. Supported by ORIP (P51OD011107, K01OD024877) and NIAID.
The Impact of SIV-Induced Immunodeficiency on Clinical Manifestation, Immune Response, and Viral Dynamics in SARS-CoV-2 Coinfection
Melton et al., bioRxiv. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680717/
The effects of immunodeficiency caused by chronic HIV infection on COVID-19 have not been directly addressed in a controlled setting. Investigators conducted a pilot study in which two pigtail macaques (PTMs) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and compared with SIV-naive PTMs infected with SARS-CoV-2. Despite the marked decrease in CD4+ T cells in the SIV-positive animals prior to exposure to SARS-CoV-2, investigators found that disease progression, viral persistence, and evolution of SARS-CoV-2 were comparable to the control group. These findings suggest that SIV-induced immunodeficiency alters the immune response to SARS-CoV-2 infection, leading to impaired cellular and humoral immunity. However, this impairment does not significantly alter the course of infection. Supported by ORIP (P51OD011104, U42OD013117, S10OD026800, S10OD030347) and NIAID.
A Combined Adjuvant Approach Primes Robust Germinal Center Responses and Humoral Immunity in Non-Human Primates
Phung et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625619/
Protein antigens require adjuvants for high immunogenicity, and delivery kinetics are a critical component of rational HIV vaccine design. Investigators employed a combined adjuvant approach (i.e., short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide, plus saponin/MPLA nanoparticles) with slow antigen delivery and potent immune-stimulating complexes in rhesus macaques of both sexes. They reported that pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells. These findings indicate that a combined adjuvant approach can augment humoral immunity by modulating immunodominance, and this work can be applied for the development of clinical therapeutics. Supported by ORIP (P51OD011104) and NIAID.
Broad Receptor Tropism and Immunogenicity of a Clade 3 Sarbecovirus
Lee et al., Cell Host and Microbe. 2023.
https://www.sciencedirect.com/science/article/pii/S1931312823004225
Investigators showed that the S glycoprotein of the clade 3 sarbecovirus PRD-0038 in the African Rhinolophus bat has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. They generated a cryogenic electron microscopy structure of the RBD bound to ACE2, explaining receptor tropism and highlighting differences between SARS-CoV-1 and SARS-CoV-2. PRD‑0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses, compared with SARS-CoV-2. These findings underline a potential molecular pathway for zoonotic spillover of a clade 3 sarbecovirus, as well as the need to develop pan-sarbecovirus vaccines and countermeasures. Supported by ORIP (S10OD032290, S10OD026959, S10OD021644), NIAID, NCI, and NIGMS.
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons et al., c. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674359/
Current HIV treatment strategies are focused on forced proviral reactivation and elimination of reactivated cells with immunological or toxin-based technologies. Researchers have proposed the use of a novel “block-lock-stop” approach, which entails the long-term durable silencing of viral expression and permanent transcriptional deactivation of the latent provirus. In the present study, the authors present this approach and its rationale. More research is needed to understand the (1) epigenetic architecture of integrated provirus, (2) cell types and epigenetic cell states that favor viral rebound, (3) molecular functions of Tat (a protein that controls transcription of HIV) and host factors that prevent permanent silencing, (4) human endogenous retrovirus silencing in the genome, and (5) approaches to generate defective proviruses. Additionally, community engagement is crucial for this effort. Supported by ORIP (K01OD031900), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS.
High Throughput Analysis of B Cell Dynamics and Neutralizing Antibody Development During Immunization With a Novel Clade C HIV-1 Envelope
Mopuri et al., PLoS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10627474/
Broadly neutralizing antibodies from chronic infection are an area of interest for HIV-1 vaccine development. Using male and female rhesus macaques, a team of researchers conducted a high-throughput longitudinal study to determine how B cells respond to vaccines expressing different HIV-1 Env immunogens. In most animals, the B cells failed to achieve neutralizing activity. One animal, however, developed neutralizing antibodies against the vaccine strain. These data suggest that early elicitation might favor the induction of neutralizing antibodies against HIV-1 Env. This work offers new insights for autologous neutralizing antibody lineages. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.