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Tracking immunoglobulin variable-gene expression in HIV infection

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Abstract

B-cell SAgs interact with normal human nonimmune immunoglobulins (Igs) independently of the light-chain isotype, and activate a large proportion of the B-cell repertoire. Recently, the major envelope protein of human immunodeficiency virus 1 (HIV-1), gp120, was found to exhibit SAg-like properties for B cells with potential pathological consequences for the infected host, including accelerated apoptosis and progressive loss of B cells. This unconventional mode of interaction contrasts with its binding to immunization-induced antibodies, which requires the tertiary structure of the heavy- and light-chain variable regions. Examining the temporal development of VH3+ antibodies in HIV-1-infected subjects over a 7-yrperiodshowed that VH3+ antibodies specific for the gp 120 SAg-binding site are deficient. Quantification of VH3+ antibodies, which impart protective responses to infectious agents, in serum samples from HIV-seropositive slow progressors and from patients who progressed to AIDS-related manifestations reveals that paucity in VH3+ antibodies is a marker of rapid clinical decline. Remarkably, anti-gp 160 VH3+ antibodies show a gradual decrease in progressors and vary with time, depending on the viral load. Thus, VH3+ antibodies could play an importantrole in protection, and their underexpression may accelerate disease progression. Investigation of the structural basis of the interaction between human Igs and gp 120 shows that the viral gp 120 SAg can interact only with a subset of human VH3+ Igs. A number of amino acid-positions present primarily in the first and third framework regions of the Ig heavychain variable regions correlate with gp 120 binding. These residues partially overlap with the Staphylococcus aureus protein A-binding site for VH3+ Igs. Overall, these interactions could represent a novel mechanism of humoral deficiency resulting from the capacity of a viral SAg to impact an important subset of the B-cell repertoire and to induce B-cell death by apoptosis.

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Zouali, M. Tracking immunoglobulin variable-gene expression in HIV infection. Appl Biochem Biotechnol 83, 13–29 (2000). https://doi.org/10.1385/ABAB:83:1-3:13

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