CYCLOSPORINE-INDUCED APOPTOSIS IN CD4(-LYMPHOCYTES AND COMPUTER-SIMULATED ANALYSIS - MODELING A TREATMENT SCENARIO FOR HIV-INFECTION() T)

Cyclosporine A (CsA) is a potent immunosuppressive drug which interfer es in vitro and in vivo with T-cell function. CsA has been shown to ar rest T-cell maturation intrathymically and to inhibit T-cell prolifera tion. In this study, we demonstrate that CsA induces apoptosis in the canine CD4(+) CD8(-) T-lymphocyte cell line 401 in a dose- and time-de pendent fashion. Similar results could also be obtained from human per ipheral blood lymphocytes. Apoptosis is observed within 4 hours after CsA application and is not prevented by excessive addition of ConA sup ernatant as a source of interleukins. The induction of apoptosis in CD 4(+) T lymphocytes suggests a possible treatment option for human immu nodeficiency virus (HIV) infections, since the major target population for the HIV would be ablated at short term. A computer-simulated anal ysis with the ''Cybermouse'' HIV model confirmed that the virus would eventually disappear and HIV-infected macrophages would also be substa ntially reduced if CsA were given in combination with drugs which bloc k viral replication (3'-azido 3'-deoxythymidine or 2',3'-dideoxycytidi ne). This treatment scenario could be applied under controlled conditi ons and with supportive patient care. A further review of the literatu re also suggests the positive impact of CsA treatment on the progressi on and outcome of AIDS-related mortality.