Protease inhibitors stimulate hematopoiesis and decrease apoptosis and ICEexpression in CD34(+) cells

Highly active retroviral therapy has been associated with a decline in the frequency of cytopenia in patients with human immunodeficiency virus (HIV) infection. This may result from lower hematologic toxicity of newer antivir al drugs and their increased efficacy against HIV-I, Protease inhibitors, i n addition to their effects on HIV replication, appear to affect various ce llular functions. Recently, it was reported that ritonavir inhibited caspas e-1 expression in normal CD4(+) cells. it was hypothesized that protease in hibitors may improve hematopoietic function owing to their direct effects o n the bone marrow progenitor cells. When ritonavir was added to methylcellu lose cultures of bone marrow cells from HIV-infected patients and normal co ntrols, colony formation increased 2.4-fold (n = 5) in control cultures and 4-fold (n = 5) in cultures of cells from HIV-infected patients. In the pre sence of ritonavir, cultures of CD34(+) cells showed markedly decreased apo ptosis in comparison with untreated cultures (45% decrease in apoptotic cel l number; n = 6). A synthetic inhibitor of caspase 1 (Ac-Tyr-Val-Ala-Asp-al dehyde [single-letter amino acid codes]), which inhibits activation of seve ral caspases including CPP32 and interleukin 1 beta -converting enzyme (ICE or caspase 1), also decreased the rate of apoptosis and enhanced colony fo rmation by progenitor cells derived from HIV-infected patients (3-fold; n = 5), In ritonavir-treated samples derived from HIV-infected individuals, th e number of cells expressing ICE also decreased. In conclusion, HIV proteas e inhibitors may, by blocking the caspase-dependent apoptotic pathway, over come inhibition of hematopoiesis seen in patients with HIV infection, an ef fect unrelated to their antiviral activity. (C) 2000 by The American Societ y of Hematology.