The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals.
Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy for suppression of HIV, but its effects on the immune system are relatively unknown. Recently, it has been reported that PIs inhibit lymphocyte apoptosis. In the present study we have investigated the effects of ex vivo addition of IDV on lymphocyte activation and apoptosis in cells from HIV-infected children (n = 18) and from healthy uninfected individuals (controls, n = 5) as well as in Jurkat and PM1 T-cell lines. Pretreatment of control peripheral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-dependent inhibition of lymphoproliferative responses to different activation stimuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phase in anti-CD3 monoclonal antibody-stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apoptosis of PBMCs from HIV-infected or uninfected individuals or of Fas-induced apoptosis in Jurkat and PM1 T cell lines were not inhibited by IDV. Moreover, IDV did not inhibit activation of caspases-1, -3, -4, -5, -9, and -8 in lysates of Jurkat T cells undergoing Fas-induced apoptosis. The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV.
Chavan
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S
Division of Allergy/Immunology, Department of Pediatrics, North Shore University Hospital, New York University School of Medicine, Manhasset, NY 11030, USA.
Kodoth
S
S
Pahwa
R
R
Pahwa
S
S
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D015658:HIV Infections / Q000097:blood*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D007223:Infant; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D019014:fas Receptor / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D019014:fas Receptor; D019469:Indinavir; D020169:Caspases