Role of B Lymphocytes In HIV Infection And Pathogenesis

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

In 2023, we pursued studies encompassing three major themes: 1) investigating B-cell dysregulation in lymphoid tissues of PLWH; 2) evaluating the clinical benefits of HIV broadly neutralizing antibodies; and 3) contributing to studies on B cells in non-HIV diseases. 1) As part of follow-up studies on the impact of HIV infection on B cells in the peripheral blood and associated populations in lymph nodes, we have concentrated our efforts on the memory B-cell (MBC) compartment which is progressively depleted in PLWH, especially those with advancing disease and chronic viremia. This depletion of MBCs, previously described in the peripheral blood, was more recently identified in lymph nodes by work in our group in collaboration with Dr. Irini Seriti in the LIR. The depletion was most pronounced in advanced disease and among IgM MBCs, the B cells that are responsible for natural immunity and the precursors of affinity-matured, immunoglobulin-switched MBCs that are responsible for long-lasting immunity against most human pathogens. By designing new strategies to directly visualize various B-cell populations in lymph node tissue sections, we have identified several alterations within the IgM MBC population in lymph nodes of PLWH with chronic HIV viremia and advanced disease. With HIV disease progression, we have found an increase in the number MBCs that express IgM in the absence of IgD, an immunoglobulin that is usually expressed with IgM. Very little is known regarding this unusual MBC population and despite limitations in enrolling new patients for this project, we have been able to use our large HIV lymphoid tissue repository to investigate where these cells reside in lymph nodes and whether they contribute to nascent immune reconstitution following initiation of ART. We are also trying to identify their B-cell counterparts in the peripheral blood, a compartment that is much more accessible for research than lymphoid tissues. 2) In follow-up studies with longtime LIR collaborator Dr. Tae-Wook Chun on the role of broad and potent anti-HIV antibodies (bNAbs) in suppressing HIV in the absence of ART, we have begun to explore how B cells contribute to the HIV-neutralizing antibody repertoire and how the virus evolves to evade the antibody response. To pursue these studies, we have identified and screened plasma from three groups of PLWH enrolled in several of our LIR observational clinical research protocols: 1) a small group of PLWH whose plasma HIV viremia appears to be controlled by autologous antibodies; 2) a small group of PLWH who develop bNAbs but whose virus is resistant to them; and 3) a large group of PLWH with varying profiles of resistance to well characterized bNAbs. From the first group, we have designed a series of in vitro assays aimed at screening PLWH plasma for the presence of IgG that suppresses autologous virus and at isolating the corresponding antibodies from sorted/cultured B cells. Thus far, we have identified one PLWH whose IgG antibodies were likely responsible for suppressing his HIV plasma viremia in the absence of ART for over three years. From the second group, we are pursuing multi-omic analyses of B cells in several PLWH who developed HIV neutralizing antibodies in the absence of ART but with detectable HIV plasma viremia. The goal is to understand the development of bNAbs despite the lack of viral control. We are also characterizing the viral bNAb resistance profiles in this group of elite neutralizers to understand the dynamics of viral escape. This latter approach is being extended to a third group of over 100 PLWH who have varying patterns of viral resistance to a panel of well characterized bNAbs that target different sites of vulnerability on the HIV envelope. While resistance to bNAbs can be a property of transmitted virus, we hypothesize that it can also develop through viral escape from autologous antibodies whose targets are very similar to those of the bNAb panel and that this is a progressive process that can be traced over time with longitudinal specimens. 3) In 2023, we have contributed to several collaborative efforts on other diseases that affect B cells with colleagues in the LIR, as well as with other laboratories at NIAID. In a study conducted by Dr. Raphaela Goldbach-Mansky in NIAID that investigated systemic inflammation due to inborn errors in the Src-family tyrosine kinase LYN, we identified several elements of B-cell dysregulation associated with the constitutive activation of the mutated LYN. The effects were found to be reversed by the Src kinase inhibitor dasatinib, demonstrating the importance of LYN in B-cell signaling and the potential for therapeutic treatment with this class of inhibitors. In a study conducted by Dr. Barbara Rehermann in NIDDK, we contributed to the evaluation of memory B-cell responses to chronic HCV infection. We also contributed to NIAID studies on m-pox in HIV infection and HIV reservoirs in elite controllers (LIR, with Dr. Tae-Wook Chun) and the role of the HIV accessory protein Nef in caspase activation (Dr. Peter Sun). The remainder of our collaborative efforts have focused on COVID-19, details of which can be found in the annual report on COVID-19 research.