Document 0126
 DOCN  M9480126
 TI    Inhibition of activation-induced programmed cell death and restoration
       of defective immune responses of HIV+ donors by cysteine protease
       inhibitors.
 DT    9410
 AU    Sarin A; Clerici M; Blatt SP; Hendrix CW; Shearer GM; Henkart PA;
       Experimental Immunology Branch, National Cancer Institute,; National
       Institutes of Health, Bthesda, MD 20892.
 SO    J Immunol. 1994 Jul 15;153(2):862-72. Unique Identifier : AIDSLINE
       MED/94292818
 AB    In vitro activation of PBLs from HIV+ individuals resulted in programmed
       cell death (PCD) within 2 days in 58 of 95 HIV+ blood donors, in
       contrast to only two of 30 control HIV- donors. CD4+ and CD8+ T cells
       from HIV+ donors died under these conditions, and these cells showed
       apoptotic nuclear morphology and DNA fragmentation. To test the
       hypothesis that this cell death shares a common biochemical pathway with
       that induced by TCR cross-linking in normal dividing T cells, inhibitors
       of the calcium-activated cysteine protease calpain were tested for their
       ability to block the activation-induced PCD of HIV+ donors. The E-64
       (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60%
       inhibition of HIV+ PCD responses, while the aldehyde inhibitors,
       leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The
       involvement of this calpain-dependent death pathway in HIV-induced
       functional T helper cell deficiency was tested by examining the effect
       of calpain inhibitors on the defective Ag- and mitogen-dependent
       proliferative responses of HIV+ donors. Twenty to fifty percent of such
       defective responses were significantly restored toward normal levels by
       calpain inhibitors, whereas control responses by normal donors were
       largely unaffected. These data suggest that a calpain-dependent PCD
       pathway contributes to HIV-associated immunodeficiency and suggest the
       use of calpain inhibitors as a possible route to therapy of HIV
       infection.
 DE    Apoptosis/*DRUG EFFECTS  Blood Donors  Calpain/*PHYSIOLOGY  Cells,
       Cultured  Cysteine Proteinase Inhibitors/*PHARMACOLOGY  Human  HIV
       Seropositivity/*IMMUNOLOGY  Lupus Erythematosus, Systemic/IMMUNOLOGY
       *Lymphocyte Transformation  T-Lymphocytes/*IMMUNOLOGY  JOURNAL ARTICLE

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