title: Resistance against Integrase Strand Transfer Inhibitors and Relevance to HIV Persistence.
abstract: Drug resistance prevents the successful treatment of HIV-positive individuals by decreasing viral sensitivity to a drug or a class of drugs. In addition to transmitted resistant viruses, treatment-naïve individuals can be confronted with the problem of drug resistance through de novo emergence of such variants. Resistant viruses have been reported for every antiretroviral drug tested so far, including the integrase strand transfer inhibitors raltegravir, elvitegravir and dolutegravir. However, de novo resistant variants against dolutegravir have been found in treatment-experienced but not in treatment-naïve individuals, a characteristic that is unique amongst antiretroviral drugs. We review here the issue of drug resistance against integrase strand transfer inhibitors as well as both pre-clinical and clinical studies that have led to the identification of the R263K mutation in integrase as a signature resistance substitution for dolutegravir. We also discuss how the topic of drug resistance against integrase strand transfer inhibitors may have relevance in regard to the nature of the HIV reservoir and possible HIV curative strategies.
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada. tibo_mes@hotmail.com.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada. mark.wainberg@mcgill.ca.|Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC H3A 2R7, Canada. mark.wainberg@mcgill.ca.|Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, QC H3A 0G4, Canada. mark.wainberg@mcgill.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D000818:Animals; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase
keywords: HIV; HIV eradication; R263K; dolutegravir; elvitegravir; integrase strand-transfer inhibitors; raltegravir; resistance; viral fitness; viral reservoirs