Selected Grantee Publications
Anti–PD-1 Chimeric Antigen Receptor T Cells Efficiently Target SIV-Infected CD4+ T Cells in Germinal Centers
Eichholtz et al., The Journal of Clinical Investigation. 2024.
https://pubmed.ncbi.nlm.nih.gov/38557496/
Researchers conducted adoptive transfer of anti–programmed cell death protein 1 (PD-1) chimeric antigen receptor (CAR) T cells in simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes on antiretroviral therapy (ART). In some macaques, anti–PD-1 CAR T cells expanded and persisted concomitant with the depletion of PD-1+ memory T cells—including lymph node CD4+ follicular helper T cells—associated with depletion of SIV RNA from the germinal center. Following CAR T infusion and ART interruption, SIV replication increased in extrafollicular portions of lymph nodes, plasma viremia was higher, and disease progression accelerated, indicating that anti–PD-1 CAR T cells depleted PD-1+ T cells and eradicated SIV from this immunological sanctuary. Supported by ORIP (U42OD011123, U42OD010426, P51OD010425, P51OD011092), NCI, NIAID, and NIDDK.
Early Antiretroviral Therapy in SIV-Infected Rhesus Macaques Reveals a Multiphasic, Saturable Dynamic Accumulation of the Rebound Competent Viral Reservoir
Keele et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38593120/
Researchers studied the dynamics of rebound-competent viral reservoir (RCVR) establishment in male and female rhesus macaques and assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of antiretroviral therapy (ART) after 1 year. All rhesus macaques rebounded between 7 and 16 days after ART, with 3 to 28 rebound lineages. Calculated reactivation rates per pre-ART plasma viral load were consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks after infection. The data highlight the heterogeneity of the RCVR between rhesus macaques, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection. Supported by ORIP (P51OD011092), NCI, and NIAID.
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.
Vaccination Induces Broadly Neutralizing Antibody Precursors to HIV gp41
Schiffner et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38816615
Primary immunogens that induce rare broadly neutralizing antibody (bnAb) precursor B cells are needed to develop vaccines against viruses of high antigenic diversity. 10E8-class bnAbs must possess a long, heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. Researchers developed germline-targeting epitope scaffolds with an affinity for 10E8-class precursors that exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens. Protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. This study showed that germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features. Supported by ORIP (P51OD011132, U42OD011023), NIAID, and NIGMS.
Natural Killer–Like B Cells Are a Distinct but Infrequent Innate Immune Cell Subset Modulated by SIV Infection of Rhesus Macaques
Manickam et al., PLOS Pathogens. 2024.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012223
Natural killer–like B (NKB) cells express both natural killer (NK) and B cell receptors. Intracellular signaling proteins and trafficking markers were expressed differentially on naive NKB cells. CD20+ NKG2A/C+ NKB cells were identified in organs and lymph nodes of naive rhesus macaques (RMs). Single-cell RNA sequencing (scRNAseq) of sorted NKB cells confirmed that NKB cells are unique, and transcriptomic analysis of naive splenic NKB cells by scRNAseq showed that NKB cells undergo somatic hypermutation and express Ig receptors, similar to B cells. Expanded NKB frequencies were observed in RM gut and buccal mucosa after simian immunodeficiency virus (SIV) infection, and mucosal and peripheral NKB cells were associated with colorectal cytokine milieu and oral microbiome changes. NKB cells gated on CD3-CD14-CD20+NKG2A/C+ cells were inclusive of transcriptomically conventional B and NK cells in addition to true NKB cells, confounding accurate phenotyping and frequency recordings. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
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.