Role of B Lymphocytes In HIV Infection And Pathogenesis

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

In 2022, we pursued studies encompassing three major themes: 1) investigating B-cell reconstitution in advanced HIV; 2) evaluating the clinical benefits of HIV broadly neutralizing antibodies; and 3) performing studies on B cells in non-HIV diseases. As part of a longstanding collaboration with Dr. Irini Seriti in the LIR, we investigated B and T cells in advanced HIV disease, under her clinical research protocol NCT02147405. The goal of the investigation, recently published in Frontiers of Immunology, was to evaluate immune reconstitution following initiation of antiretroviral therapy (ART) in individuals with advanced HIV disease. Participants underwent lymph node biopsies at the time of enrollment and again 6-8 weeks post ART. These paired biopsies offered a unique opportunity to investigate immunologic changes that occur over a short period of time after the immune system begins to recover from advanced HIV disease. Several important insights gained may have implications for other immune deficiencies. However, given the complexity of advanced HIV disease, we needed to identify which factors were associated with immune reconstitution and which were associated with advanced HIV disease itself. The changes in B and T cells following initiation of ART and reduction in viremia suggest that both factors were at play during the period of analysis. One unexpected observation among B cells was the expansion in advanced disease of a population of memory B cells that expressed IgM as the B-cell receptor in the absence the other isotype, IgD, that is usually expressed with IgM. Very little is known regarding this unusual population of memory B cells 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. In the second major theme, we contributed to a major study on the role of combination anti-HIV antibodies in suppressing HIV in the absence of ART. This was the culmination of a clinical trial undertaken in 2018 and abruptly terminated by COVID-19. Nonetheless, the results, recently published in Nature, clearly demonstrated that the passive transfer of a combination of two highly potent and broadly neutralizing antibodies against HIV were highly effective at maintaining HIV viral suppression for up to 43 weeks after treatment interruption, a period that was significantly longer than in the placebo group. The study made several important observations with implications for future passive therapeutic interventions, including that a dual combination of broad and potent neutralizing antibodies can provide long-term HIV suppression in the absence of ART but only if patients harbor virus that is sensitive to the antibody cocktail. This study revealed that many patients have resistant virus and a major goal over the upcoming year will be to investigate potential mechanisms that underpin the development of resistant virus. One possibility is that resistance arises as the virus evolves to evade autologous B-cell and antibody responses. We will be addressing this possibility with samples from our longitudinal cohorts. In the third major theme, we have contributed to several collaborative efforts on HIV and other diseases of the immune system with colleagues in the LIR, as well as with other laboratories at NIAID. In 2022, these efforts have focused on COVID-19, details of which can be found in the annual report on COVID-19 research.