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* Department of Medicine, Division of Infectious Diseases, and
Department of Cellular and Structural Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA; and
Holland Laboratory, Plasma Derivatives Department, American Red Cross, Rockville, Maryland 20855, USA
1Correspondence: Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262, USA. E-mail: leland.shapiro{at}uchsc.edu
Several observations suggest the existence of potent endogenous
suppressors of human immunodeficiency virus type 1 (HIV-1) production,
and inhibitors of serine proteases may participate in this effect.
Alpha-1-antitrypsin (AAT) is the most abundant circulating serine
protease inhibitor. Physiological AAT concentrations inhibited HIV-1
production in chronically infected U1 monocytic cells, reduced virus
replication in freshly infected peripheral blood mononuclear cells, and
blocked infection of permissive HeLa cells. In U1 cells, AAT suppressed
activation of the HIV-1-inducing transcription factor NF-
B. Similar
results were obtained using CE-2072, a synthetic inhibitor of host
serine proteases. HIV-1 did not replicate in blood obtained from
healthy volunteers, but marked replication was observed in blood from
individuals with hereditary AAT deficiency. These results identify AAT
as a candidate circulating HIV-1 inhibitor in vivo. Two
different mechanisms of AAT-induced HIV-1 inhibition were identified,
including reduced HIV-1 infectivity and blockade of HIV-1 production. A
novel host–pathogen interaction is suggested, and an alternative
strategy to treat HIV-1-related disease may be possible.—Shapiro, L.,
Pott, G. B., Ralston, A. H. Alpha-1-antitrypsin inhibits
human immunodeficiency virus type 1.
Key Words: alpha-1-proteinase inhibitor • serine proteinase inhibitors • HIV-1 • NF-kappa B • interleukin 18
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