Reviews and feature article
Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease

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HIV disease is associated with abnormalities in all major lymphocyte populations, including B cells. Aberrancies in the B-cell compartment can be divided into 3 broad categories: changes that arise as a result of HIV-induced immune activation, changes that arise as a result of HIV-induced lymphopenia, and changes that arise independently of these 2 parameters. We review recent developments in all 3 categories of abnormalities and highlight how observations made in the early years of the HIV epidemic are better understood today in large part because of the advent of effective antiretroviral therapy. Insight into the mechanisms of B-cell dysfunction in HIV disease has also been achieved as a result of increased knowledge of the B-cell subpopulations as they exist in healthy individuals, compared with their abnormalities in HIV-infected individuals. A better understanding of the pathogenic mechanisms of B-cell abnormalities in HIV disease can potentially lead to new strategies for improving antibody responses against opportunistic pathogens that afflict HIV-infected individuals and against HIV itself, in the context of both HIV infection and an antibody-based HIV vaccine.

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B-cell hyperactivation in HIV disease

Many features of B-cell dysregulation in HIV disease suggest a prominent role for aberrant immune activation. These features include elevated serum levels of immunoglobulins and autoantibodies,6 extensive expansion in B-cell areas of lymphoid tissue,7, 8 and an increased expression of activation, proliferation, and terminal differentiation markers on circulating B cells.5, 9, 10, 11 As illustrated in Fig 1 and in data not shown, terminal differentiation of B cells is associated with a loss in

Direct interactions between HIV and B cells

Although there is little evidence that HIV productively infects B cells in vivo, we have shown that B cells isolated from the blood and lymph nodes of HIV-infected individuals carry replication-competent virus on their surface.21 The interaction is mediated primarily through the binding of complement-opsonized HIV virions to CD21 expressed on the surface of B cells. These findings are consistent with other in vivo and in vitro studies demonstrating a prominent role for CD21 in the trapping of

Changes in B-cell subpopulations in HIV disease

Many of the B-cell aberrations that have been reported in HIV disease are likely to reflect alterations in the frequencies of the various subpopulations of B cells that are present in the human body, or at least that are detectable in the peripheral blood (Table I). Given that the vast majority of these studies have been performed on B cells isolated from the peripheral blood, we restrict our comments to alterations in this compartment. Naive B cells constitute the largest B-cell subpopulation

Increased B-cell death in HIV disease

Cell death by apoptosis is an important component of immune activation and lymphocyte depletion in HIV disease.46 Two major pathways of apoptosis exist: the intrinsic pathway arises from an insufficiency in survival factors that result in mitochondrial-driven apoptosis, whereas the extrinsic pathway arises from the triggering of a death receptor.47 In HIV disease, both these pathways likely contribute to increased B-cell death,18, 48 and B-cell depletion that we and others have documented.35, 49

Functional alterations of B cells in HIV disease

The effects of HIV infection on B-cell function can be divided into 2 broad categories. The first category relates to changes that directly reflect in vivo phenomena, such as hypergammaglobulinemia, increased autoantibody levels, and poor antibody responses to specific antigens. The second category relates to changes that are inferred from ex vivo analysis of B cells isolated from HIV-infected individuals. There have been substantial advances in the latter category over the period of the past

Conclusion

In summary, HIV infection in a majority of untreated individuals leads to persistent viral replication and progressive CD4+ T-cell lymphopenia. Persistent HIV replication is associated with increased immune activation that manifests itself in the B-cell compartment as hypergammaglobulinemia, polyclonal B-cell activation, induction of terminal differentiation of B cells, increased levels of autoantibodies, and increased frequency of B-cell malignancies. CD4+ T cell lymphopenia and increased

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    (Supported by an educational grant from Merck & Co., Inc.)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Terms in boldface and italics are defined in the glossary on page 13.

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