Hyper activation of the immune system has emerged as an important clinical marker of HIV disease progression to AIDS. During the chronic phase of the disease, chronic immune activation is linked to systemic CD4 T-cell depletion and eventual immune failure. Additionally, the HIV virus per se seems to engage in a form of molecular parasitism for host T-cell signaling pathways and transcription factors (e.g. NFAT). Targeting host T-cell factors that mediate immune activation in conjunction with HAART (Highly Active Antiretroviral Therapy) could be the basis of novel immune-modulatory regimens that avoid the development of mutant viral strains. Hence the three-signal model of T-cell activation provides a framework for the rational selection of immunomodulatory therapies in HIV disease. Within this framework we examine the immunosuppressive, and antiretroviral properties of NFAT (calcineurin) inhibitors (cyclosporine and tacrolimus), the purine rescue pathway inhibitor mycophenolate mofetil and sirolimus (rapamycin). The results of small clinical studies to date are reviewed and they suggest that immunosuppressive medications might be a safe and effective adjunct to HAART in stable HIV disease, when such medications are used in full doses. Finally, we discuss the potential implications of such therapies for solid organ transplantation in HIV patients.
Keywords: AIDS, HAART, immunosuppression, T-cells, CD4, transcription factors, NFAT, calcineurin, cyclosporine, tacrolimus/FK506
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