Selected Grantee Publications
- 666 results found
Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge with Simian-Tropic HIV
Swanstrom et al., EBioMedicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/37625266
Lenacapavir is a U.S. Food and Drug Administration–approved drug for treating multidrug-resistant HIV and needs to be taken only twice a year. Preexposure prophylaxis (PrEP) is a form of medicine that protects a person from getting sick rather than having to treat them after they get a disease. Because lenacapavir shows long-acting drug activity, it may be an ideal candidate for PrEP, as current PrEP medications require daily dosing. Researchers used experiments in vitro (in the lab, outside of a living organism) to show that lenacapavir has strong antiviral activity. Using 4- to 9-year-old male nonhuman primates (NHPs), researchers showed that a single dose of lenacapavir injected beneath the skin protected the NHPs from simian-tropic HIV-1 virus. After 419 days, researchers depleted T cell (a type of immune cell) levels in the NHPs and showed that low-level viral infections did not emerge. This study supports the evidence for moving lenacapavir into human PrEP development. Supported by ORIP (U42OD011123, P40OD028116), NCI, and NIAID.
Development and Validation of an Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry Method for Quantifying Lenacapavir Plasma Concentrations: Application to Therapeutic Monitoring
West III et al., Journal of Chromatography B. 2023.
https://pubmed.ncbi.nlm.nih.gov/37866010
Antiretroviral therapy (ART) is used to treat patients with HIV. Lenacapavir is a U.S. Food and Drug Administration–approved ART. Following initial doses of lenacapavir taken orally and injected beneath the skin, the patient gives themselves a dose by injection once every 6 months. With this long-acting and infrequent dosing, patients may need to be monitored to ensure that proper drug levels are achieved in the body to prevent viral mutations that could cause drug resistance. Researchers developed a novel mass spectrometry (a tool to measure molecules in a sample) method to test the effectiveness of ART by measuring lenacapavir levels in human plasma. The researchers validated the new method using a large range of clinically relevant doses. The results showed that the method is precise and consistent. This suggests that the method can monitor lenacapavir levels in human plasma and evaluate ART effectiveness in clinical settings. Supported by ORIP (S10OD028540) and NIAID.
Long-Acting Lenacapavir Acts as an Effective Preexposure Prophylaxis in a Rectal SHIV Challenge Macaque Model
Bekerman et al., Journal of Clinical Investigations. 2023.
https://pubmed.ncbi.nlm.nih.gov/37384413
Preexposure prophylaxis (PrEP) is a form of medicine that protects a person from getting a disease rather than having to treat them after they get sick. Daily oral PrEP is an effective way to prevent new HIV infections, but it must be taken as instructed. PrEP that requires less-frequent doses would make it easier and more convenient to keep taking the medication and would reduce clinical visits. Using 3- to 5-year-old male nonhuman primates, researchers showed that a single dose of lenacapavir injected beneath the skin produced sustained levels of the drug in plasma. It also provided strong preventive activity against a high-dose simian-human immunodeficiency virus (SHIV) administered rectally. No drug resistance emerged, and SHIV infections occurred only when the drug level fell below the target needed for complete protection. These findings give researchers critical data about dosing intervals, protective concentrations, and the long-acting potential of lenacapavir. This knowledge will support lenacapavir’s progression to human HIV PrEP trials. Supported by ORIP (U42OD021458).
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.
Single-Component Multilayered Self-Assembling Protein Nanoparticles Presenting Glycan-Trimmed Uncleaved Prefusion Optimized Envelope Trimers as HIV-1 Vaccine Candidates
Zhang, Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082823/
Researchers are interested in engineering protein nanoparticles to mimic virus-like particles for an HIV-1 vaccine. In this study, researchers explored a strategy that combines HIV envelope glycoprotein (Env) stabilization, nanoparticle display, and glycan trimming. They designed a panel of constructs for biochemical, biophysical, and structural characterization. Using female mice, female rabbits, and rhesus macaques of both sexes, they demonstrated that glycan trimming increases the frequency of vaccine responders and steers antibody responses away from immunodominant glycan holes and glycan patches. This work offers a potential strategy for overcoming the challenges posed by the Env glycan shield in vaccine development. Supported by ORIP (P51OD011133, P51OD011104, U42OD010442) and NIAID.
Vpr Attenuates Antiviral Immune Responses and Is Critical for Full Pathogenicity of SIVmac239 in Rhesus Macaques
Laliberté et al., iScience. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10679897/
The accessory viral protein R (Vpr) exhibits multilayered functions, and more work is needed to understand its roles in viral replication, immune evasion, and pathogenicity in vivo. Using male and female rhesus macaques, researchers examined how deletion of vpr affects simian immunodeficiency virus (SIV) replication kinetics, innate immune activation, B- and T-cell responses, and neutralizing activity. They found that lack of Vpr delays and attenuates viral replication during acute infection, allowing most animals to mount efficient and persisting immune responses and higher levels of neutralizing antibodies. Overall, these results suggest that Vpr promotes viral replication and innate immune evasion during acute SIV infection. Supported by ORIP (P51OD011133, P51OD011132, S10OD026799).
Deep Analysis of CD4 T Cells in the Rhesus CNS During SIV Infection
Elizaldi et al., PLOS Pathogens. 2023.
https://pubmed.ncbi.nlm.nih.gov/38060615/
Systemic HIV infection results in chronic inflammation that causes lasting damage to the central nervous system (CNS), despite long-term antiretroviral therapy (ART). Researchers studied neurocognitive outcomes in male and female rhesus macaques infected with simian immunodeficiency virus (SIV) using an ART regimen simulating suboptimal adherence; one group received no ART, and the other received ART with periodic interruptions. Using single-cell transcriptomic profiling, the researchers also identified molecular programs induced in the brain upon infection. They found that acute infection led to marked imbalance in the CNS CD4/CD8 T‑cell ratio, which persisted into the chronic phase. The studies provide insight into the role of CD4 T cells in the CNS during HIV infection. Supported by ORIP (P51OD011107, K01OD023034), NIA, NIAID, and NCI.
Cholera Toxin B Scaffolded, Focused SIV V2 Epitope Elicits Antibodies That Influence the Risk of SIVmac251 Acquisition in Macaques
Rahman et al., Frontiers in Immunology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37153584/
Previous work has indicated that the production of antibodies against epitopes in the V2 loop of gp120—a protein component of the viral spikes used to infiltrate host cells—correlates with protection from viral acquisition. Researchers assessed the efficacy of a simian immunodeficiency virus (SIV) vaccine consisting of a V2c epitope scaffolded onto cholera toxin B in rhesus macaques of both sexes. Immunized animals generated V2c-specific antibody responses, and differences in the functional antibody and immune cell responses were observed and compared with responses in a historically protective vaccine regimen. Different responses also were observed when varying adjuvants were administered with the vaccines. Thus, full protection against SIV infection might require vaccines against multiple spike epitopes. Supported by ORIP (P51OD011104, R24OD010976) and NIAID.
Simian Immunodeficiency Virus and Storage Buffer: Field-Friendly Preservation Methods for RNA Viral Detection in Primate Feces
Wilde et al., mSphere. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10732032/
Simian immunodeficiency virus (SIV) infects more than 40 nonhuman primate (NHP) species in sub-Saharan Africa, but testing in wild NHP populations can be challenging. Researchers compared methods for SIV RNA preservation and recovery from NHP fecal samples stored in four different buffers. The goal of this work was to identify a robust “field-friendly” method (i.e., without freezing or refrigeration) for this effort, and the samples were collected from a mantled guereza colobus housed at the Columbus Zoo and Aquarium. The authors reported that the DNA/RNA shield is an optimal buffer for preserving SIV RNA in fecal samples in the field. Their findings will inform future fieldwork and facilitate improved approaches for studies of SIV and other RNA viruses. Supported by ORIP (P51OD011132) and NIAID.
Lymphoid Tissues Contribute to Plasma Viral Clonotypes Early After Antiretroviral Therapy Interruption in SIV-Infected Rhesus Macaques
Solis-Leal et al., Science Translational Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/38091409/
Researchers are interested in better understanding the sources, timing, and mechanisms of HIV rebound that occurs after interruption of antiretroviral therapy (ART). Using rhesus macaques (sex not specified), investigators tracked barcoded simian immunodeficiency virus (SIV) clonotypes over time and among tissues. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. Additionally, the authors reported that CD4+ T cells harbored the most viral RNA after ART interruption. These tissues are likely to contribute to viral reactivation and rebound after ART interruption, but further studies are needed to evaluate the relative potential contributions from other tissues and organs. Supported by ORIP (P51OD011104, P51OD011133, S10OD028732, S10OD028653), NCI, NIMH, and NINDS.