HIV-1, NFAT, and cyclosporin: immunosuppression for the immunosuppressed?
The human immunodeficiency virus-1 (HIV-1), the cause of AIDS, remains a significant cause of morbidity and mortality throughout the planet. Although reverse transcriptase and protease inhibitors have substantially slowed the virus, viral resistance complicates therapy. Because HIV-1 relies on its host's transcriptional machinery for its own replication, strategies for targeting activation-dependent transcription factors in CD4 T cells are being considered for adjunctive therapy in HIV-1-infected individuals. The nuclear factor of activated T cells (NFAT) family of transcription factors is one such target. On T-cell stimulation, NFAT proteins translocate to the nucleus, where they activate a large number of early response genes, including cytokines such as interleukin-2. Activation and nuclear translocation of NFAT proteins are abrogated by the powerful immunosuppressants cyclosporin A (CsA) and FK506. Over the last several years, various investigators have demonstrated that NFAT proteins bind to the HIV-1 LTR promoter and increase viral transcription. In this report, further evidence supporting a role for NFAT proteins in augmenting HIV-1 transcription is presented. In addition, other mechanisms of HIV-1 inhibition by CsA are reviewed, and the rationale for the use of CsA to treat AIDS is discussed.
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Division of Rheumatology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Philadelphia 19104, USA. rqcron@mail.med.upenn.edu
D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D016559:Tacrolimus