HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells

Objective: Clinical experience with HIV-1 protease inhibitors (PIs) in the treatment of AIDS frequently has shown that increases in CD4+ T-cell counts can be independent of HIV-1 inhibition by these drugs. This disconnection between viral load and CD4 counts led us to investigate how the PI ritonavi r directly affects leukocyte activation in vitro, using peripheral blood mo nonuclear cell (PBMC) fractions derived from normal donors. Methods and Results: When uninfected PBMC cultures were treated for 72 hour s with ritonavir at concentrations similar to or lower than that shown to b e effective in vivo, an increase in cell viability was observed. The suscep tibility of PBMCs to apoptosis was markedly decreased after ritonavir treat ment and correlated with lower levels of caspase-1 expression, decreases in annexin V staining, and reduced caspase-3 activity. Induction in vitro of tumor necrosis factor (TNF) production by PBMCs and monocytes was inhibited by ritonavir in a time- and dose-dependent manner at nontoxic concentratio ns. Conclusion: Based on our data, we conclude that the HIV-1 PI ritonavir is a n immune modulator that may affect leukocyte activation and apoptosis as an important part of its therapeutic benefit.