In order to evaluate the potential utility of ATIII as a salvage agent in patients with multidrug resistant HIV, we assessed the ability of hep-ATIII to inhibit a range of drug-resistant HIV-1 isolates in vitro, and in humanized mice infected with highly drug resistant HIV-1. In addition, we studied the A 943931 dihydrochloride effects of ATIII treatment in rhesus macaques chronically infected with SIV. In a novel therapeutic approach, we used anti-HLA-DR antibodies engrafted into immunoliposomes to encapsulate hep-ATIII : it has been shown that these immunoliposomes specifically target HLA-DR positive cells in lymph nodes including monocytes, macrophages and activated CD4 + T lymphocytes, allowing concentration of therapeutic ATIII in the main cellular reservoirs of HIV and SIV. Finally, we sought to understand the mechanism by which hep-ATIII exerts its antiviral activity. We studied the gene expression profiles of peripheral blood mononuclear cells from SIV-infected macaques treated with hep-ATIII, and identified the transcriptional networks activated or repressed by hep-ATIII treatment. By elaborating the biologic networks associated with HIV inhibition by the innate immune system, we hoped to identify potential biomarkers of drug efficacy, as well as potential future drug targets. All animal experimental protocols were approved by the Harvard Institutional Animal Care and Use Committee. Human blood sampling was reviewed and approved by the Human Research Ethics Committee of the Beth Israel Deaconess Medical Center and Harvard Medical School. Written consent for human blood collection was waived since no personal data were collected. Harvard Medical School follows NIH guidelines for animal handling and has Animal Welfare Assurance A3153-01 on file with the Office for Protection of Research Risks. The institutions involved in the studies maintain full accreditation from Association for Assessment and Accreditation of Laboratory Animal Care. Adult rhesus macaques were housed at the New England 6bK primate Research Center and Harvard Medical School, a primate animal facility that is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International. Research was conducted in compliance with the Animal Welfare Act and other US federal statutes and regulations relating to animals and experiments involving animals, and adhered to principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996. All steps were taken to ameliorate the welfare and to avoid the suffering of the animals in accordance with the ����Weatherall report for the use of non-human primates���� recommendations. Animals were housed either socially or in adjoining individual primate cages allowing social interactions, under controlled conditions of humidity, temperature and light. Food and water were available ad libitum. Animals were fed commercial monkey chow and treats by trained personnel.