Nonrandom features of the human immunoglobulin variable region gene repertoire expressed in response to HIV-1

Characterization of the immune response toward HIV is important for understanding the basic mechanisms of the disease and may give essential information for development of an anti-HIV vaccine. Paradoxically, although HIV infection is associated with a strong antibody response to structural and nonstructural HIV proteins, this immune response does not seem to halt disease progression. Both quantitative and qualitative B-cell abnormalities are associated with disease progression. The immunological abnormalities in HIV-1 infection include abnormal cytokine production and expansion of HIV-1-specific B-cell precursors that may reach 40%. There is also evidence that gp120 exerts a B-cell superantigen-like activity on human B-cells through binding to gene products of the third heavy-chain variable region family (VH3). This property of gp120 may induce abnormal mechanisms of selection of the antibody repertoire. It may also account for the apparent paucity of anti-gp120 antibodies expressing VH3 genes and for the polyclonal activation seen in the early stages of HIV infection. This expansion would reflect specific stimulation of VH3 B-cells, but not all B-cells. It would then be followed by a significant deletion of this B-cell subset. Finally, autoimmune phenomena have been described in HIV infection, and several hypotheses have been put forward to account for such associations. On the basis of the superantigen concept discussed above, one may suggest that gp120 may trigger B-cell subsets bearing receptors with specificities for self-components. This would explain the multiplicity of autoantibody specificities seen in this disease.