We also found that six genes and 7 loci were down regulated at both time points after therapy. Serpins are induced rapidly following virus infection as part of a complex host innate immune response. Mounting clinical evidence demonstrates an association between increased levels of serpin expression and either reduced HIV acquisition in uninfected individuals or delayed disease progression in chronically infected individuals. For example, serpins have been found to be present at high levels in the cervical fluids of uninfected but repeatedly HIV-1 exposed sex workers. ATIII, a serpin with functions in the coagulation cascade, was shown to have antiviral activity in vitro against not only HIV but HCV and HSV as well. We are beginning to recognize that the serpins may have broad roles in the innate immune response, which in the case of ATIII includes an anti-inflammatory function in sepsis, anti-angiogenesis in tumor growth, and chemotaxis for neutrophils, human peripheral blood lymphocytes and monocytes. The role of serpins as adjuvants of the innate immune system may A 350619 hydrochloride suggest a potentially novel application for serpins in antiviral therapy. Although the arsenal of small molecule HIV inhibitors continues to grow, drug resistance remains an important obstacle to long-term HIV therapy. Modulators of the innate immune system are attractive therapeutics because they act indirectly on the virus through multiple host pathways, and so are not as vulnerable to the evolution of viral resistance mutations. Indeed, our results suggest that ATIII may be an effective part of a salvage regimen for patients with highly drug resistant HIV strains. We also found that when appropriately modified and targeted through liposomal encapsulation, hep-ATIII 8-(3-Chlorostyryl)caffeine appears to be very safe, with a favorable TI.100 and no obvious negative effects in murine and nonhuman primate models. Our experiments suggest that the precise biochemical modification and packaging of ATIII is critical to its therapeutic utility. It is well described that the various biological functions of ATIII are dependent on its tertiary structure. This structure-de-pendent functionality of ATIII holds true for its ability to inhibit HIV as well. Interestingly, in vitro, heparin-activated ATIII and the thrombin-ATIII complex showed the highest level of HIV-1 inhibition, followed by pre-latent ATIII. A relaxed form of ATIII has a 50% reduced inhibitory activity, whereas HIV inhibition in vitro is negligible for the L-isoforms of ATIII. In vivo as well, ATIII antiviral activity appears to be dependent on biochemical modification: CD8 + T cells of HIV long-term nonprogressors exhibit enhanced ability to activate ATIII that may be partially responsible for the reported non-cytolytic inhibition of HIV-1 in this cohort. ATIII is predominately in its S-configuration in blood at a physiological concentration of about 2.4 mM.