title: In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes.
abstract: Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log(10) reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America. masmal@partners.org
authors.forename: Mohammed
authors.initials: M
authors.lastname: Asmal
authors.forename: James B
authors.initials: JB
authors.lastname: Whitney
authors.forename: Corinne
authors.initials: C
authors.lastname: Luedemann
authors.forename: Angela
authors.initials: A
authors.lastname: Carville
authors.forename: Robert
authors.initials: R
authors.lastname: Steen
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Ralf
authors.initials: R
authors.lastname: Geiben-Lynn
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy*; D006493:Heparin / Q000737:chemistry*; D008081:Liposomes / Q000378:metabolism; D008196:Lymph / Q000378:metabolism*; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015843:Serpins / Q000737:chemistry; D014779:Virus Replication
chemical_list: D008081:Liposomes; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D000990:Antithrombin III; D006493:Heparin