B cells in HIV infection and disease

Abstract

In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4(+) T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction.

Figure 1. HIV-induced alterations of human B-cell subpopulations

As immature CD19⁺CD20⁺ B cells exit the bone marrow, a small fraction can be identified in the peripheral blood by the expression of CD10 in the absence of CD27. The frequency of these immature transitional B cells, which can be further divided into CD21^low and CD21^hi subsets, is increased in the peripheral blood of HIV-infected individuals, probably as a result of the increased serum levels of interleukin-7 (IL-7) that are associated with HIV-induced CD4⁺ T-cell lymphopenia (a). Chronic HIV viraemia is associated with the expansion of several B-cell subpopulations, including activated mature B cells that have downregulated their expression of CD21 and express CD27, short-lived Ki-67⁺ plasmablasts that have downregulated their expression of CD20 and CD21 and express high levels of CD27, and tissue-like memory B cells that have downregulated their expression of CD21, do not express CD27 and have several features of virus-induced exhaustion (listed in FIG. 3) (b). HIV infection is associated with a loss of resting memory B cells (defined by the expression of CD21 and CD27) that is not reversed by antiretroviral therapy (c).

Figure 2. Direct and indirect effects of HIV replication on B cells

Direct effects of HIV virions or viral proteins on B cells include the binding of complement-bound HIV virions to B cells through the complement receptor CD21, which can enhance virus dissemination and increase B-cell depletion by apoptosis. Binding of HIV virions or gp120 can also induce B cells to secrete inflammatory cytokines, such as tumour necrosis factor (TNF) and interleukin -6 (IL-6). In addition, secreted Nef from sites of HIV replication can diffuse into B cells and suppress B-cell class switch recombination. Moreover, HIV-infected macrophages release factors, some of which are secreted in a Nef-dependent mechanism (such as ferritin), that stimulate B cells. Indirect effects of ongoing HIV replication in infected individuals are the result of HIV-induced immune-cell activation and CD4⁺ T-cell depletion. Increased serum levels of IL-7 are associated with CD4⁺ T-cell lymphopenia, increased B-cell immaturity and decreased responses to antigen. Various systemic mediators of immune-cell activation and increased cell turnover have been proposed, including lipopolysaccharide (LPS), B-cell-activating factor (BAFF), TNF, interferon-α (IFNα), IL-6 and IL-10. IFN-stimulated genes are strongly induced in B cells of HIV-viraemic individuals, probably as a result of chronic immune-cell activation. LPS is released as a result of microbial leakage from HIV-induced intestinal tissue damage (not shown). Serum levels of BAFF are increased in HIV infection, although the source of increased secretion is unknown.

Figure 3. B-cell exhaustion induced by persistent HIV infection and ongoing viral replication

In the context of self-limiting viral infections, naive B cells respond to exogenous antigen by migrating to T-cell-rich areas of lymphoid tissues, becoming activated, initiating a germinal centre reaction that selects for B cells with improved antigen binding and finally exiting the germinal centre as either long-lived resting memory B cells or plasma cells. In the context of a persistent viral infection such as HIV, chronic immune activation increases the frequency of antigen-experienced B cells that are short-lived and have undergone several cell divisions. The chronic immune activation induced by HIV also gives rise to exhausted B cells that have a shortened replication history and decreased immunoglobulin diversity, consistent with the increased expression of multiple inhibitory receptors and altered expression of homing receptors that favour migration to sites of inflammation and away from sites of cognate B-cell–T-cell interactions. The exhausted B cells have poor proliferative responses, but are enriched for virus-specific responses.

Timeline

Highlights of research into HIV pathogenesis with implications for B cells