CROSS-LINKING OF FAS BY ANTIBODIES TO A PECULIAR DOMAIN OF GP120 V3 LOOP CAN ENHANCE T-CELL APOPTOSIS IN HIV-1-INFECTED PATIENTS

Previous studies have demonstrated that T cell-reactive antibodies in HIV-1 infection contribute to lymphocyte depletion by cytotoxicity tha t involves differential membrane targets, such as the 43.5-kD receptor on CEM cells. Here, we show that these antibodies bind Fas as result of a molecular mimicry of the gp120. Both now cytometry and immunoblot ting using the human Fas-transfected mouse WC8 lymphoma revealed posit ive binding of immunoglobulin G from several patients to a 43.8-kD mem brane receptor that also reacts with the CH11 anti-Fas monoclonal anti body. Specificity to Fas was further confirmed to chimeric recombinant human Fas-Fc by ELISA, whereas overlapping peptide mapping of a Fas d omain (VEINCTR-N) shared by gp120 V3 loop demonstrated a predominant a ffinity to the full-length 10-mer peptide. Four anti-Fas affinity prep arations greatly increased the subdiploid DNA peak of CEM cells simila r to agonist ligands of Fas. In addition, anti-Fas immunoglobulin G st rongly inhibited the [H-3]thymidine uptake of CEM cells in proliferati ve assays, inducing a suppression as high as provoked by both CH11 mAb and recombinant human Fas ligand. Since anti-Fas were reactive to gp1 20, it is conceivable that antibodies binding that domain within the V 3 region are effective cross-linkers of Fas and increase apoptosis in peripheral T cells. These results suggest gest that autologous stimula tion of the Fas pathway, rather than of lymphocytotoxic antibodies, ma y aggravate lymphopenia in a number of HIV-1(+) subjects.