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.
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-1beta (IL-1beta)-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.
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
E M
EM
Sloand
P N
PN
Kumar
S
S
Kim
A
A
Chaudhuri
F F
FF
Weichold
N S
NS
Young
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D020170:Caspase 1 / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D019014:fas Receptor / Q000276:immunology
D017320:HIV Protease Inhibitors; D019014:fas Receptor; D020170:Caspase 1; D019438:Ritonavir