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 fo r suppression of HIV, but its effects on the immune system are relatively u nknown. Recently, it has been reported that Pls inhibit lymphocyte apoptosi s, In the present study we have investigated the effects of ex vivo additio n 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 periphe ral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-depe ndent inhibition of lymphoproliferative responses to different activation s timuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phas e in anti-CD3 monoclonal antibody-stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apopt osis 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. Moreov er, 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 in dicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis, It is concluded that IDV may prolong c ell survival indirectly by inhibiting their entry into cell cycle. In indiv iduals on PI therapy, PI-mediated effects could potentially modulate immuno logic responses independently of antiviral activity against HIV, (C) 2001 b y The American Society of Hematology.