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Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.

A Sarin, M Clerici, S P Blatt, C W Hendrix, G M Shearer and P A Henkart
J Immunol July 15, 1994, 153 (2) 862-872;
A Sarin
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M Clerici
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S P Blatt
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C W Hendrix
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G M Shearer
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P A Henkart
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Abstract

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.

  • Copyright © 1994 by American Association of Immunologists
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The Journal of Immunology
Vol. 153, Issue 2
15 Jul 1994
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Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.
A Sarin, M Clerici, S P Blatt, C W Hendrix, G M Shearer, P A Henkart
The Journal of Immunology July 15, 1994, 153 (2) 862-872;

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Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.
A Sarin, M Clerici, S P Blatt, C W Hendrix, G M Shearer, P A Henkart
The Journal of Immunology July 15, 1994, 153 (2) 862-872;
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Print ISSN 0022-1767        Online ISSN 1550-6606