To determine whether modification of ATIII has an effect on in vivo therapeutic HIV activity, we assessed three forms of the protein: non-3-Deazaneplanocin A hydrochloride activated ATIII, heparin-activated ATIII – both given intravenously – and liposomally encapsulated ATIII given subcutaneously. Nonactivated ATIII, at a concentration sufficient to reduce inflammation in a baboon model of sepsis, and at 10�C20-fold normal physiologic concentrations, did not impede viral replication. In vitro experiments had demonstrated that the anti-HIV activity of ATIII could be enhanced through heparin activation, and in concordance with this we found that intravenous administration of hep-ATIII resulted in a modest inhibition of viral replication in vivo, confirming the importance of ATIII activation. However, we observed the most potent inhibition of plasma virus when ATIII was packaged in immunoliposomes and delivered subcutaneously. There are several possible explanations for this observation: It is likely that unencapsulated hep-ATIII is not specifically transported to lymph nodes, a tissue that harbors viral replication, while in contrast, anti-HLA-DR immunoliposomes likely transport ET-ATIII to this location. Follicular dendritic cells may stimulate viral replication in lymphocytes, and it has been demonstrated that serpins may interfere with this process. HIV disease progression is associated with ATIII deficiency in blood. Nevertheless, there is likely considerable circulating anti-HIV serpin activity in plasma, such that the serpin anti-HIV activity in plasma may be saturated, and intravenous inoculation of hep-ATIII into the plasma has limited additive effect. In contrast subcutaneous administration of ET-ATIII targeting lymphoid organs maybe more effective because baseline serpin activity in lymphoid organs is minimal. We probed the underlying mechanism of hep-ATIII anti-HIV activity using software-supported interactome analysis, which allowed us to identify key host cell factors that are immediately downstream of drug treatment, and which in turn modulate the expression of overarching gene networks. We previously found that hep-ATIII activated two interactomes in HIV-1 infected PBMC: one interactome dependent on the NFkB transcription factor and a second interactome anchored by ERK1/2. These host factors are known to significantly impact HIV-1 replication. We now have expanded our analysis of transcriptional changes downstream of treatment with hep-ATIII, and studied these changes in the significantly more complex in vivo environment. Once again we found networks regulated by NFkB and ERK1/2-PTGS2 associated with hep-ATIII treatment confirming earlier in vitro results from PBMC acutely infected with HIV-1. There is a great need to ACET counter HIV-induced inflammation and its consequences on the central nervous system including HIV dementia.