Molecular determinants of the human antibody response to HIV-1: implications for disease control

Various aspects of the immune response to HIV-1 infection remain unclear. While seropositive subjects generally mount a strong humoral response, the antibodies produced are not effective in halting disease progression. Molecular characterization of the antibody repertoire specific for HIV-1 antigens represents an approach to further our understanding of the mechanisms involved in mounting a humoral immunity in this infection. Recently, the content, structure, and organization of the human immunoglobulin-variable gene loci have been elucidated and a number of laboratories have characterized the variable gene elements of human anti-HIV-1 antibodies derived from infected persons by cell fusion or by Epstein-Barr virus transformation. The results show evidence for extensive somatic mutations that lead to preferential amino acid substitutions in the hypervariable regions, an indication of an antigen-driven process. Multiple other molecular events also are engaged in generating antibody diversity, including various types of fusions of variable genes, usage of inverted diversity genes, and addition of extragenomic nucleotides. Most importantly, there is a paucity of antibodies expressing the major V(H)3 gene family, which could result from the capacity of gp120 to act as superantigen for human B cells. This V(H)3+ antibody deficit also has been observed in B cells isolated ex vivo from the patients. Since V(H)3+ antibodies play an essential role in immune defense against infections, the abnormalities observed in HIV-1 infection may predispose to opportunistic infections and further compromise the immune defense mechanisms of the subjects.