title: Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
abstract: Human immunodeficiency virus type 2 (HIV-2) is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and exhibits reduced susceptibility to several of the protease inhibitors used for antiretroviral therapy of HIV-1. Thus, there is a pressing need to identify new classes of antiretroviral agents that are active against HIV-2. Although recent data suggest that the integrase strand transfer inhibitors raltegravir and elvitegravir may be beneficial, mutations that are known to confer resistance to these drugs in HIV-1 have been reported in HIV-2 sequences from patients receiving raltegravir-containing regimens. To examine the phenotypic effects of mutations that emerge during raltegravir treatment, we constructed a panel of HIV-2 integrase variants using site-directed mutagenesis and measured the susceptibilities of the mutant strains to raltegravir and elvitegravir in culture. The effects of single and multiple amino acid changes on HIV-2 replication capacity were also evaluated. Our results demonstrate that secondary replacements in the integrase protein play key roles in the development of integrase inhibitor resistance in HIV-2. Collectively, our data define three major mutational pathways to high-level raltegravir and elvitegravir resistance: i) E92Q+Y143C or T97A+Y143C, ii) G140S+Q148R, and iii) E92Q+N155H. These findings preclude the sequential use of raltegravir and elvitegravir (or vice versa) for HIV-2 treatment and provide important information for clinical monitoring of integrase inhibitor resistance in HIV-2-infected individuals.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America. smithra@u.washington.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.forename: Dana N
authors.initials: DN
authors.lastname: Raugi
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pan
authors.forename: Matthew
authors.initials: M
authors.lastname: Coyne
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hernandez
authors.forename: Brad
authors.initials: B
authors.lastname: Church
authors.forename: Kara
authors.initials: K
authors.lastname: Parker
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Papa Salif
authors.initials: PS
authors.lastname: Sow
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Gottlieb
mesh_terms: D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015498:HIV-2 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011760:Pyrrolidinones / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D015398:Signal Transduction / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir