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M9480126.TXT
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1994-08-09
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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
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).