The main biologic function of serpins is the blockage of protease activity involved in blood clotting and complement activation. Serpins belong to a superfamily of proteins that also regulate other inflammatory processes. Serine protease inhibitors have a broad spectrum of anti-viral activity against HIV, HCV, HSV and the influenza virus. A number of clinical observations suggest a role for the serpins in controlling HIV infection and disease progression in the mucosa and the peripheral blood. For example, there is a barrier to HIV transmission via the oral mucosa; this may be due to the antiviral activity of Secretory Leukocyte Inhibitor in saliva. a1-anti-trypsin, the most abundant serpin in blood, prevents HIV replication in vitro at physiological concentrations; in addition, HIV replicates at a much higher rate in the blood of a1-antitrypsin- deficient individuals, suggesting a1-anti-trypsin might reduce viral replication in vivo. The anti-HIV activity of a1- anti-trypsin is believed to be responsible for the relatively low transmission rates of HIV through contaminated needles, ACBC compared to that of HCV and HBV. Furthermore, presence of the a1-anti-trypsin allelic variants M2 and A332A is associated with enhanced HIV-1 acquisition. Antithrombin III, a serpin with a role in the coagulation cascade, exhibits potent anti-HIV activity. ATIII exists in three different forms under physiological conditions. In its inactive latent form, ATIII circulates with its reactive COOH-terminal loop not fully exposed, thereby preventing its binding to thrombin. Upon binding to heparin, ATIII undergoes a 22-Oxacalcitriol conformational change to an activated, or stressed form allowing the exposure of the reactive COOH-terminal loop thus increasing the binding of thrombin by 100-fold. The resultant ATIII-thrombin complex eventually dissociates with the release of thrombin and an ATIII with a cleaved reactive loop, inducing a conformational change of ATIII to a relaxed form. A proteolytically cleaved form of ATIII was originally discovered to be a CD8 + T cell anti-HIV factor – a noncytolytic innate immune response in HIV-1 long-term nonprogressors. The S form of ATIII has greater antiviral activity against HIV and the simian immunodeficiency virus than the R form; the L form has no anti-viral activity. Hep- ATIII is up to 10-fold more potent at inhibiting HIV than the nonactivated form of ATIII. When compared to other serpins with anti-HIV activity, a1-antitrypsin and SLPI, heparin-activated antithrombin III displays up to 106 fold higher anti- HIV activity in vitro. The anti-viral activity of hep-ATIII and ATIII is mediated at least in part by host cell factors prostaglandin synthetase 2 and transcription factor NFkB. Two hundred-fold less hep-ATIII was required as compared to non-activated ATIII to elicit equivalent changes in gene transcription of these host cell factors. In the present study, we sought to validate hep-ATIII as an HIV therapeutic using in vitro, humanized mouse and preclinical primate models of HIV infection.