title: Simian-tropic HIV as a model to study drug resistance against integrase inhibitors.
abstract: Drug resistance represents a key aspect of human immunodeficiency virus (HIV) treatment failure. It is important to develop nonhuman primate models for studying issues of drug resistance and the persistence and transmission of drug-resistant viruses. However, relatively little work has been conducted using either simian immunodeficiency virus (SIV) or SIV/HIV recombinant viruses for studying resistance against integrase strand transfer inhibitors (INSTIs). Here, we used a T-cell-tropic SIV/HIV recombinant virus in which the capsid and vif regions of HIV-1 were replaced with their SIV counterparts (simian-tropic HIV-1 [stHIV-1](SCA,SVIF)) to study the impact of a number of drug resistance substitutions in the integrase coding region at positions E92Q, G118R, E138K, Y143R, S153Y, N155H, and R263K on drug resistance, viral infectivity, and viral replication capacity. Our results show that each of these substitutions exerted effects that were similar to their effects in HIV-1. Substitutions associated with primary resistance against dolutegravir were more detrimental to stHIV-1(SCA,SVIF) infectiousness than were resistance substitutions associated with raltegravir and elvitegravir, consistent with data that have been reported for HIV-1. These findings support the role of stHIV-1(SCA,SVIF) as a useful model with which to evaluate the role of INSTI resistance substitutions on viral persistence, transmissibility, and pathogenesis in a nonhuman primate model.
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wares
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Said
authors.initials: S
authors.lastname: Hassounah
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.affiliation: National HIV and Retrovirology Laboratory, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Ontario, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sandstrom
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada mark.wainberg@mcgill.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D000818:Animals; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir