Selected Grantee Publications
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- 175 results found
- HIV/AIDS
- Women's Health
Physiologically Based Pharmacokinetic Model Validated to Enable Predictions of Multiple Drugs in a Long-Acting Drug-Combination Nano-Particles (DcNP): Confirmation With 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products
Perazzolo et al., Journal of Pharmaceutical Sciences. 2024.
https://jpharmsci.org/article/S0022-3549(24)00060-1/fulltext
Drug-combination nanoparticles synchronize delivery of multiple drugs in a single, long-acting, targeted dose. Two distinct classes of long-acting injectable products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site, and Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access. This review used data from three nonhuman primate studies, consisting of nine pharmacokinetic data sets, to support clinical development of Class II products. Eight of nine models passed validation, and the drug–drug interaction identified in the ninth model can be accounted for in the final model. Supported by ORIP (P51OD010425, U42OD011123), NIAID, and NHLBI.
Persistence of a Skewed Repertoire of NK Cells in People With HIV-1 on Long-Term Antiretroviral Therapy
Anderko et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551350
HIV-1 infection alters the natural killer (NK) cell phenotypic and functional repertoire. A rare population of FcRγ−NK cells exhibiting characteristics of traditional immunologic memory expands in people with HIV. In a longitudinal analysis during the first 4 years of antiretroviral therapy (ART), a skewed repertoire of cytokine unresponsive FcRγ−memory-like NK cells persisted in people with HIV, and surface expression of CD57 and KLRG1 increased, suggesting progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing antibody titers to human cytomegalovirus (CMV), with human CMV viremia detected in approximately one-third of people studied during the first 4 years of ART. About 40% of people studied displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis. These findings indicate that NK cell irregularities persist in people with HIV despite long-term ART. Supported by ORIP (P51OD011132, S10OD026799), NIAID, and NHLBI.
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
SIV Infection Is Associated With Transient Acute-Phase Steatosis in Hepatocytes In Vivo
Derby, Viruses. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10892327/
Metabolic dysfunction–associated fatty liver disease (MAFLD) in people with HIV has become an increasing concern, but little is known about liver-specific changes underlying HIV-related MAFLD. Using rhesus macaques (sex not specified), researchers examined the timing of pathogenic changes within the liver during simian immunodeficiency virus (SIV) infection. Their findings suggest differential pathologies associated with the acute and chronic phases of infection. This work highlights the early damage inflicted on the liver by SIV/HIV infection and indicates that damage to the hepatocytes plays a specific role. Overall, the authors conclude that therapeutic interventions targeting metabolic function may benefit liver health in people who have recently received an HIV diagnosis. Supported by ORIP (P51OD011107, P51OD011092) and NIAID.
Potent Antibody-Dependent Cellular Cytotoxicity of a V2-Specific Antibody Is Not Sufficient for Protection of Macaques Against SIV Challenge
Grunst et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38252675/
Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with decreased risk of HIV acquisition. Researchers tested the ability of PGT145, an antibody that neutralizes genetically diverse HIV-1 isolates, to protect rhesus macaques against simian immunodeficiency virus (SIV) via ADCC activity. They found that a single amino acid substitution in the V2 core epitope of the SIV envelope increases PGT145 binding and confers sensitivity to neutralization. Peak and chronic phase viral loads were lower, and time to peak viremia was delayed. They concluded that ADCC is insufficient for protection by this antibody, but increasing the affinity of antibody binding could confer partial protection. Supported by ORIP (P51OD011106), NIAID, and NCI.
SHIV-C109p5 NHP Induces Rapid Disease Progression in Elderly Macaques with Extensive GI Viral Replication
Bose et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38299866/
Researchers are interested in developing animal models infected with simian–human immunodeficiency virus (SHIV) to better understand prevention of HIV acquisition. Researchers generated pathogenic SHIV clade C transmitted/founder stock by in vivo passage using geriatric rhesus macaques of both sexes. They reported that the infection resulted in high sustained viral loads and induced rapid pathology and wasting, necessitating euthanasia between 3 and 12 weeks post-infection. The extensive viral replication in gut and lymphoid tissues indicated a fit viral stock. This work provides a new nonhuman primate model for HIV pathogenicity and cure studies. Supported by ORIP (R24OD010947) and NIDDK.
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.
Induction of Durable Remission by Dual Immunotherapy in SHIV-Infected ART-Suppressed Macaques
Lim et al., Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/38422185/
The latent viral reservoir is established within the first few days of HIV infection and remains a barrier to a clinical cure. Researchers characterized the effects of a combined Anktiva (N-803) treatment with broadly neutralizing antibodies (bNAbs) using male and female rhesus macaques infected with simian–human immunodeficiency virus infection. Their data suggest that these agents synergize to enhance CD8+ T-cell function, particularly when multiple bNAbs are used. Taken together, this work indicates that immune-mediated control of viral rebound is not a prerequisite for sustained remission after discontinuation of antiretroviral therapy and that immune-mediated control of viral rebound is achievable, sufficient, and sustainable in this model. Supported by ORIP (P51OD011106, P40OD028116, R24OD011195) and NIAID.
TGF-β Blockade Drives a Transitional Effector Phenotype in T Cells Reversing SIV Latency and Decreasing SIV Reservoirs In Vivo
Kim et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/38355731/
Interruption of antiretroviral therapy leads to rapid rebound of viremia due to the establishment of a persistent viral reservoir early after infection. Using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases simian immunodeficiency virus (SIV) reactivation, and reduces the viral reservoir in female rhesus macaques. Their findings reveal a galunisertib-driven shift toward an effector phenotype in T and natural killer cells. Taken together, this work demonstrates that galunisertib, a clinical-stage TGF-β inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in the absence of toxicity. Supported by ORIP (R24OD010947), NIAID, and NCI.
Effect of Hormone Replacement Therapy on Amyloid Beta (Aβ) Plaque Density in the Rhesus Macaque Amygdala
Appleman et al., Frontiers in Aging Neuroscience. 2024.
https://www.frontiersin.org/articles/10.3389/fnagi.2023.1326747/full
Amyloid beta plaque density is associated with Alzheimer’s disease. In this study, the authors examined its concentration in aged female nonhuman primates’ cerebrospinal fluid, as well as in the amygdala, an area of the brain involved with emotion and memory. They set out to test the hypothesis that estrogen hormone replacement therapy can beneficially affect amygdala Aβ plaque density in “surgically menopausal” females (i.e., aged rhesus macaques that had undergone ovariectomy). Female rhesus macaques that received estrogen replacement therapy showed fewer amyloid plaques than those that did not receive the hormone. This effect was observed regardless of the type of diet that the animals consumed. These findings suggest that hormone replacement might be a helpful treatment to consider for Alzheimer’s disease. Supported by ORIP (P51OD011092, R24OD011895, S10OD025002) and NIA.