Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1

Several observations suggest the existence of potent endogenous suppressors of human immunodeficiency virus type 1 (HIV-l) production, and inhibitors of serine proteases may participate in this effect. Alpha-1-antitrypsin (AA T) is the most abundant circulating serine protease inhibitor. Physiologica l AAT concentrations inhibited HIV-1 production in chronically infected U1 monocytic cells, reduced virus replication in freshly infected peripheral b lood mononuclear cells, and blocked infection of permissive HeLa cells, In U1 cells, AAT suppressed activation of the HIV-1-inducing transcription fac tor NF-kappaB. Similar results were obtained using CE-2072, a synthetic inh ibitor 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 infe ctivity and blockade of HIV-1 production. A novel host-pathogen interaction is suggested, and an alternative strategy to treat HIV-1-related disease m ay be possible.