Cyclosporine-induced apoptosis in CD4 + T lymphocytes and computer-simulated analysis: modeling a treatment scenario for HIV infection

Abstract

Cyclosporine A (CsA) is a potent immunosuppressive drug which interferes in vitro and in vivo with T-cell function. CsA has been shown to arrest T-cell maturation intrathymically and to inhibit T-cell proliferation. In this study, we demonstrate that CsA induces apoptosis in the canine CD4+ CD8- T-lymphocyte cell line 401 in a dose- and time-dependent fashion. Similar results could also be obtained from human peripheral blood lymphocytes. Apoptosis is observed within 4 hours after CsA application and is not prevented by excessive addition of ConA supernatant as a source of interleukins. The induction of apoptosis in CD4+ T lymphocytes suggests a possible treatment option for human immunodeficiency virus (HIV) infections, since the major target population for the HIV would be ablated at short term. A computer-simulated analysis with the "Cybermouse" HIV model confirmed that the virus would eventually disappear and HIV-infected macrophages would also be substantially reduced if CsA were given in combination with drugs which block viral replication (3'-azido 3'-deoxythymidine or 2',3'-dideoxycytidine). This treatment scenario could be applied under controlled conditions and with supportive patient care. A further review of the literature also suggests the positive impact of CsA treatment on the progression and outcome of AIDS-related mortality.