Role of B Lymphocytes In HIV Infection And Pathogenesis

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

In 2025, we pursued studies encompassing three major themes: 1) investigating B-cell function in lymphoid tissues of PWH; 2) exploring the development of HIV-neutralizing antibodies in PWH; and 3) contributing to studies on B cells in non-HIV diseases. 1) In 2025, we pursued spatial transcriptomic and phenotypic profiling of lymphoid tissues of PWH who develop anti-HIV broadly neutralizing antibodies (bNAbs) with goal of addressing how lymphoid architecture and cellular interactions affect this process. Serum collected from PWH who underwent lymph node biopsies under a clinical research protocol, ClinicalTrials.gov identifier NCT00001316, was screened for the presence of bNAbs with a global panel of HIV envelope-pseudotyped viruses developed for this purpose. In partnership with investigators in NCI, NICHD and the NIAID core, we used the 10X Genomics Visium platform to evaluate the spatial transcriptomic differences between four pairs of lymphoid tissue specimens from PWH who developed or not bNAbs. Given the fragility of the specimens that may limit discovery, the imaging platform CODEX for multiplexed phenotyping was also developed with the NCI Collaborative Protein Technology Resource (CPTR). This is an approach that is more likely to succeed given that protein is more stable than RNA in our clinical specimens. In addition, we have performed extensive screening of longitudinal serum samples collected from our observational cohort of PWH enrolled in clinical research protocol with ClinicalTrials.gov identifier NCT00039689 and we have identified an additional eight pairs of peripheral blood mononuclear cells (PBMCs) of PWH who developed or not bNAbs over the same period and with similar demographics. These samples are currently being analyzed by single-cell multi-omics with objective of identifying signatures of bNAb development. 2) Over the past year, we have almost completed the first phase of a long-standing collaboration with Dr. Tae-Wook Chun in the LIR on the role of B cells and the HIV antibodies they produce in suppressing HIV and the and how the virus evolves to evade the antibody response. To pursue these studies, we have identified and screened plasma from three groups of PWH enrolled in several of our LIR observational clinical research protocols: 1) a small group of PWH whose plasma HIV viremia appears to be controlled by autologous antibodies; 2) a small group of PWH who develop bNAbs but whose virus is resistant to them; and 3) a large group of PWH with varying profiles of resistance to well characterized bNAbs. From the first group, we have identified an early-treated PWH, PT30, who stopped ART after 6.5 years as part of the placebo arm of an earlier intervention study that included an analytical treatment interruption phase and whose antibodies likely contributed to the viral suppression he maintained in the absence of ART for almost four years (after which he experienced superinfection with virus that was resistant to his prior and contemporary antibodies and restarted ART). We found two related lineages of B cells that were present at all timepoints over the ART-free period and produced antibodies, either cloned or secreted into culture supernatant that potently suppressed the virus of PT30 but not other HIV strains, thus these antibodies are not bNAbs. The autologous neutralizing antibody activity was evaluated in vitro with live virus and pseudoviruses expressing HIV envelopes cloned from PT30, as well as in vivo in a humanized mouse model developed by Dr. Alonso Heredia at the University of Maryland (UMD). In partnership with another UMD collaborator, Dr. Yuxing Li, we have used site-directed mutagenesis and cryo-electron microscopy to identify epitopes in the silent face of gp120 as being the targets of the two lineages of antibodies with potent autologous neutralizing activity. In addition, the binding of these antibodies to HIV envelope of PT30 expressed on infected or transfected cells was enhanced by the presence of cell-surface CD4, either in cis or in trans. These unique properties may explain the potency of the antibodies that may have prevented viral escape and contributed to the prolonged suppression of virus in the absence of ART in PT30. 3) In 2025, we contributed to several collaborative efforts on HIV and other diseases that affect B cells. In partnership Dr. Richard Davey in the LIR, we used a flow cytometry panel that we had designed for probing B-cell responses to SARS-CoV-2 mRNA vaccination to evaluate B-cell responses to a recombinant Vesicular Stomatitis Virus-based vaccine containing the Zaire ebolavirus (EBOV) glycoprotein. The participants were enrolled in PREPARE (ClinicalTrials.gov Identifier: NCT02788227), a placebo-controlled study that evaluated the safety and immunogenicity of administering a booster dose of the EBOV vaccine 18 months after the primary dose (co-authorship). In a follow-up study using specimens from the trial, we found that the primary dose of the EBOV vaccine elicited a predominantly IgM B-cell response, consistent with prior reporting of the antibody response. However, while the booster dose induced a short-lived B cell response driven by IgG, again similar in isotype to the antibody response, the antibody response was significantly stronger in the boosted than placebo group at end of study while the B-cell response was not. Thus, this vaccine strategy appears to favor the establishment of long-live plasma cells (responsible for serologic antibodies) over memory B cells, which contrasts with the more balanced outcome that has been described for mRNA vaccines. These findings have been submitted for publication in a manuscript that combines B-cell data from the NIH and antibody data from at the FDA (Dr. Surender Khurana lead investigator). Finally, we have also contributed to NIAID studies on viral reservoirs and therapeutic interventions in PLWH (LIR, with Dr. Tae-Wook Chun), and to a multi-institute NIH study on the role of epigenetics in B cell remodeling during tumorigenesis (Dr. Ivan Ovcharenko, NLM, senior author).