In vitro and in vivo effects of HIV protease inhibitors on apoptosis.
Development of potent inhibitors of HIV protease has revolutionized the treatment of HIV infection. HIV protease inhibitors (PI) have caused more dramatic improvements in CD4 T-cell numbers than in other therapies that were available previously, prompting investigators to assess whether PI possess intrinsic immunomodulatory effects. An emerging body of data indicates that HIV PIs are antiapoptotic, although the exact molecular target responsible for this antiapoptotic effect remains to be defined in vitro and in vivo. Paradoxically, high-dose PI also may have proapoptotic effects, particularly when assessed in vitro in transformed cell lines and implanted mouse models. Future research will define molecular targets of PI that are responsible for their apoptotis modulatory effects (both pro- and anti-apoptotic). In addition, evaluation of the clinical utility of PI-based therapy in those non-HIV disease states that are characterized by excessive apoptotis will reveal the full clinical potential of this intriguing class of drugs.
Badley
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Translational, Immunology and Biodefense Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. badley.andrew@mayo.edu
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000187:drug effects*; D016516:CD4-CD8 Ratio; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D016333:HIV Protease / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity
D061945:Caspase Inhibitors; D011480:Protease Inhibitors; D002154:Calpain; D020169:Caspases; D016333:HIV Protease