B-cell responses to HIV infection

Abstract

The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate, and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV.

Keywords: HIV; B cells; HIV-specific humoral immunity; pathogenesis; persisting viremia.

Fig. 1. Changes in B-Cell development and differentiation associated with HIV infection

Different B-cell populations are shown with their defining and/or useful immunophenotypic markers as they begin development in the bone marrow, continue to develop and differentiate in the periphery (peripheral blood and lymph node illustrated), and return to the bone marrow as terminally differentiated plasma cells. Alterations that occur in the various B-cell compartments of HIV-infected individuals are indicated in red text.

Fig. 2. New strategies for investigating HIV-specific B cells and harnessing their therapeutic potential

Analyses of B cells and sera from large groups of HIV-infected individuals are performed to address immunopathogenic (left box) or therapeutic/vaccine (right box) questions. Left box on immunologic studies: use of probe-based flow cytometry can be used to investigate memory B-cell responses to HIV antigens (WT-gp140), sub-specificities within HIV antigens (upper left quadrant of WT-gp140 by gp140ΔCD4bs gives frequency of B cells specific for gp140-CD4bs), as well as non HIV antigens (influenza and tetanus). Responses are typically reported by gating on cells that express the pan B-cell marker CD20 and the Ig isotype IgG and can be delineated by subset based on various B-cell markers such as CD21 and CD27. Right box on HIV bNAb studies: typically, a few individuals are identified as good candidates by screening serum from a large group of individuals for bNAb activity. Cloning of corresponding bNAbs from candidate IgG⁺ B cells proceeds with either probes-base single-cell sorting or a culture method. Examples of bNAbs isolated by each method are given and referenced in the main text, and advantages and disadvantages of each method are listed.