title: Preclinical evaluation of HIV eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase.
abstract: Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored.
authors.affiliation: Department of Medicine, University of California, San Francisco, California 94110, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Dunham
authors.forename: Shari N
authors.initials: SN
authors.lastname: Gordon
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lifson
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D010865:Pilot Projects; D010949:Plasma / Q000821:virology; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D016896:Treatment Outcome; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019562:Viral Load
chemical_list: D004279:DNA, Viral; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012367:RNA, Viral; C028129:tryptophan methyl ester; D014364:Tryptophan