Selected Grantee Publications
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- 68 results found
- Infectious Diseases
- 2023
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.
CD8+ T Cells Control SIV Infection Using Both Cytolytic Effects and Non-Cytolytic Suppression of Virus Production
Policicchio et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589330/
HIV continuously evades and subdues the host immune responses through multiple strategies, and an understanding of these strategies can help inform research efforts. Using a mathematical model, investigators assessed whether CD8+ cells from male rhesus macaques exert a cytolytic response against infected cells prior to viral production. Their goal was to elucidate the possible mode of action of CD8+ cells on simian immunodeficiency virus (SIV)–infected cells. Models that included non‑cytolytic reduction of viral production best explained the viral profiles across all macaques, but some of the best models also included cytolytic mechanisms. These results suggest that viral control is best explained by the combination of cytolytic and non-cytolytic effects. Supported by ORIP (P40OD028116, R01OD011095), NIAID, NIDDK, and NHLBI.
Timing of Initiation of Anti-Retroviral Therapy Predicts Post-Treatment Control of SIV Replication
Pinkevych et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558076/
Researchers are interested in approaches to reducing viral rebound following interruption of antiretroviral therapy, but more work is needed to understand major factors that determine the viral “setpoint” level. Researchers previously assessed how timing of treatment can affect the frequency of rebound from latency. In the current study, the authors analyzed data from multiple studies of simian immunodeficiency virus (SIV) infection in rhesus macaques to further explore the dynamics and predictors of post-treatment viral control. They determined that the timing of treatment initiation was a major predictor of both the level and the duration of post-rebound SIV control. These findings could help inform future treatments. Supported by ORIP (U42OD011023, P51OD011132, P51OD011092), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS
AZD5582 Plus SIV-Specific Antibodies Reduce Lymph Node Viral Reservoirs in Antiretroviral Therapy–Suppressed Macaques
Dashti et al., Nature Medicine. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579098/
Researchers are interested in targeting the HIV reservoir via a latency reversal and clearance approach. Previously, investigators demonstrated that AZD5582 induces systemic latency reversal in rhesus macaques and humanized mice, but a consistent reduction in the viral reservoir was not observed. In the current study, they combined AZD5582 with four simian immunodeficiency virus (SIV)–specific rhesus monoclonal antibodies using rhesus macaques of both sexes. They reported a reduction in total and replication-competent SIV DNA in lymph node–derived CD4+ T cells in the treated macaques. These findings provide proof of concept for the potential of the latency reversal and clearance HIV cure strategy. Supported by ORIP (P51OD011132, R01OD011095), NIAID, NCI, and NHLBI.