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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2735-2739
HEMATOPOIESIS
Protease inhibitors stimulate hematopoiesis and decrease
apoptosis and ICE expression in CD34+ cells
Elaine M. Sloand,
Jaroslaw Maciejewski,
Princy Kumar,
Sonnie Kim,
Aniruddho Chaudhuri, and
Neal Young
From the National Heart, Lung and Blood Institute,
National Institutes of Health, Bethesda, MD, and the Division of
Infectious Diseases, Georgetown University Medical Center,
Washington, DC.
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 antiviral drugs and their increased efficacy against HIV-1.
Protease inhibitors, in addition to their effects on HIV replication,
appear to affect various cellular functions. Recently, it was
reported that ritonavir inhibited caspase-1 expression in
normal CD4+ cells. It was hypothesized that protease
inhibitors may improve hematopoietic function owing to their direct
effects on the bone marrow progenitor cells. When ritonavir was added
to methylcellulose cultures of bone marrow cells from HIV-infected
patients and normal controls, 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 presence of ritonavir, cultures of
CD34+ cells showed markedly decreased apoptosis in
comparison with untreated cultures (45% decrease in apoptotic cell
number; n = 6). A synthetic inhibitor of caspase 1 (Ac-Tyr-Val-Ala-Asp-aldehyde [single-letter amino acid codes]), which
inhibits activation of several caspases including CPP32 and interleukin
1 -converting enzyme (ICE or caspase 1), also
decreased the rate of apoptosis and enhanced colony formation by
progenitor cells derived from HIV-infected patients (3-fold; n = 5).
In ritonavir-treated samples derived from HIV-infected individuals, the
number of cells expressing ICE also decreased. In conclusion, HIV
protease inhibitors may, by blocking the caspase-dependent apoptotic
pathway, overcome inhibition of hematopoiesis seen in patients with HIV
infection, an effect unrelated to their antiviral activity.
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