J. Exp. Med.
© The Rockefeller University Press
0022-1007/96/12/2287/14 $2.00
Volume 184 December 1996 2287-2300

Cross-linking of Fas By Antibodies to a Peculiar Domain of gp120 V3 Loop Can Enhance T Cell Apoptosis in HIV-1-infected Patients

By Franco Silvestris,^* Shigekazu Nagata, Paola Cafforio,^* Nicola Silvestris,^* and Franco Dammacco^*

From the ^* Department of Biomedical Sciences and Human Oncology, University of Bari, Section of Internal Medicine, 70124 Bari, Italy; and  Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565, Japan

Previous studies have demonstrated that T cell-reactive antibodies in HIV-1 infection contribute to lymphocyte depletion by cytotoxicity that 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 flow cytometry and immunoblotting using the human Fas-transfected mouse WC8 lymphoma revealed positive binding of immunoglobulin G from several patients to a 43.8-kD membrane receptor that also reacts with the CH11 anti-Fas monoclonal antibody. Specificity to Fas was further confirmed to chimeric recombinant human Fas-Fc by ELISA, whereas overlapping peptide mapping of a Fas domain (VEINCTR-N) shared by gp120 V3 loop demonstrated a predominant affinity to the full-length 10-mer peptide. Four anti-Fas affinity preparations greatly increased the subdiploid DNA peak of CEM cells similar to agonist ligands of Fas. In addition, anti-Fas immunoglobulin G strongly inhibited the [³H]thymidine uptake of CEM cells in proliferative assays, inducing a suppression as high as provoked by both CH11 mAb and recombinant human Fas ligand. Since anti-Fas were reactive to gp120, it is conceivable that antibodies binding that domain within the V3 region are effective cross-linkers of Fas and increase apoptosis in peripheral T cells. These results suggest that autologous stimulation of the Fas pathway, rather than of lymphocytotoxic antibodies, may aggravate lymphopenia in a number of HIV-1⁺ subjects.

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