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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1021-1027
Human Immunodeficiency Virus Type 1 Protease Inhibitor Modulates
Activation of Peripheral Blood CD4+ T Cells and Decreases
Their Susceptibility to Apoptosis In Vitro and In Vivo
Elaine M. Sloand,
Princy N. Kumar,
Sonnie Kim,
Aniruddho Chaudhuri,
Frank F. Weichold, and
Neal S. Young
From the National Heart, Lung and Blood Institute, National
Institutes of Health, Bethesda, MD; the Division of Infectious
Diseases, Georgetown University, Washington, DC; and the Institute of
Human Virology, University of Maryland, Baltimore, MD.
CD4+ T cells from patients with human immunodeficiency
virus (HIV) infection undergo apoptosis at an increased rate, which leads to their depletion during disease progression. Both the Fas-Receptor (Fas-R) and interleukin-1 (IL-1)-converting enzyme (ICE; caspase 1) appear to play a role in the mechanism of apoptosis of
CD4+ lymphocytes. Although Fas-R is upregulated on both
CD4+ and CD8+ cells in HIV-infected
patients, results from our laboratory and others indicate that, in
patients with advanced disease, CD4+ cells preferentially
express ICE. Protease inhibitors have successfully halted the
progression of HIV disease and increased CD4+ T counts.
In this study, we examined the effect of protease inhibitors on Fas-R
(CD95), ICE (caspase 1) expression, apoptosis, and cell death in
CD4+ T cells of (1) HIV-infected patients who were
receiving protease inhibitors, and (2) normal and patient
CD4+ T cells cultured with a protease inhibitor in vitro.
Fifteen patients with advanced HIV disease on treatment showed
dramatically decreased CD4+ T-cell ICE expression,
diminished apoptosis, and increased numbers of CD4+ cells
within 6 weeks of institution of protease inhibitor therapy, and before
down-modulation of Fas-R (CD95) expression was evident. To determine
the role of HIV infection, we studied the effect of ritonavir, a
protease inhibitor, on normal and patient cells in vitro. Stimulated
and unstimulated normal CD4+ T cells, cultured with
protease inhibitor, demonstrated markedly decreased apoptosis and ICE
expression (P = .01). While Fas-R expression was not
significantly altered during short-term culture by such treatment,
Fas-Ligand (Fas-L) membrane expression of phytohemagglutinin (PHA)-stimulated blood lymphocytes was decreased by protease inhibitor. In the presence of ritonavir, CD4+ T cells from
HIV-infected patients showed similar changes in ICE intracellular
levels without alteration of Fas expression. In conclusion, protease
inhibitors appear to decrease CD4+ T-cell ICE expression
and apoptosis before they affect Fas-R expression in HIV-infected
patients. This action was independent of HIV infection, as similar
effects were seen in CD4+ T cells from normal controls.
Some of the benefit of protease inhibitors may be related to
modification of programmed cell death, which increases
CD4+ T-cell number. Whether this is due to directly to
the changes effected in the caspase system remains to be determined.
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