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- HIV/AIDS
- Women's Health
Understanding Early HIV-1 Rebound Dynamics Following Antiretroviral Therapy Interruption: The Importance of Effector Cell Expansion
Phan et al., PLOS Pathogens. 2024.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012236
Researchers developed dynamic models of virus–immune interactions, building on a prior theoretical framework, to investigate the dynamics of HIV-1 rebound following antiretroviral therapy (ART). These models were evaluated using viral load data from 24 patients (sex not specified) following ART interruption. Of these models, the best-performing model highlighted that individuals with a higher effector cell expansion rate maintain viral remission for extended periods post-ART. The findings indicate that effector cell expansion plays a critical role in viral rebound control. These results suggest the potential for viral dynamic models to predict and understand HIV-1 rebound after ART interruption, contributing to the development of targeted HIV treatment strategies. Supported by ORIP (R01OD011095) and NIAID.
Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome
Lloyd, Mammalian Genome. 2024.
https://pubmed.ncbi.nlm.nih.gov/39254744
The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).
Dual Blockade of IL-10 and PD-1 Leads to Control of SIV Viral Rebound Following Analytical Treatment Interruption
Pereira Ribeiro et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39266691
Pereira Ribeiro et al. tested a hypothesis that blockading two immune molecules, IL-10 and PD‑1, following treatment interruption could help control viral rebound in antiretroviral therapy (ART)–treated rhesus macaques infected with simian immunodeficiency virus (SIV), a nonhuman analogue of HIV. When measured at 24 weeks following treatment interruption, durable control of viral rebound was seen in 9 of 10 combo-treated macaques. The investigators also found that they could predict the control of viral rebound based on the induction of inflammatory cytokines, proliferation of effector CD8+ T cells, and reduced expression of BCL-2 in CD4+ T cells prior to treatment interruption. These results could provide a way to achieve long-lasting control of HIV infection after discontinuing ART. Supported by ORIP (U42OD011023, P51OD011132), NCI, and NIAID.
Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Nelson et al., Science Immunology. 2024.
https://www.science.org/doi/10.1126/sciimmunol.adm7097
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env—SOSIP—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut. Supported by ORIP (P51OD011107), NCI, and NIAID.
Modeling Resistance to the Broadly Neutralizing Antibody PGT121 in People Living With HIV-1
Cassidy et al., PLOS Computational Biology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551976/
PGT121 is a broadly neutralizing antibody that demonstrated potent antiviral activity in an early clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants (sex unspecified), and the rebound viruses were entirely resistant to PGT121-mediated neutralization. However, two participants experienced long-term antiretroviral therapy–free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Mathematical models showed the importance of the relative fitness difference between PGT121-sensitive and -resistant subpopulations prior to treatment. Researchers identified the treatment-induced competitive advantage of a resistant population as a primary driver of resistance and emphasized the high neutralization ability of PGT121 in both participants who exhibited long-term viral control. Supported by ORIP (R01OD011095) and NIAID.
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.