title: Q148N, a Novel Integrase Inhibitor Resistance Mutation Associated with Low-Level Reduction in Elvitegravir Susceptibility.
abstract: The integrase strand transfer inhibitor (INSTI)-resistance mutations Q148H/K/R are arguably the most important INSTI-resistance mutations as they represented the first step to high-level dolutegravir cross-resistance. We describe an individual with transmitted four-class drug resistance whose virus sequence had the previously uncharacterized mutation Q148N. Infectious molecular HIV-1 clones containing Q148N alone and in combination with G140S demonstrated ∼2.4-4.5 reduced elvitegravir susceptibility depending on the virus's genetic context but retained susceptibility to raltegravir and dolutegravir. This level of reduced elvitegravir susceptibility is lower than that observed with Q148H/K/R and in fact the infected individual responded to an initial treatment regimen containing tenofovir/emtricitabine/elvitegravir/cobicistat. Q148N was associated with a higher replication capacity than Q148H, suggesting that this mutation may be more fit in the absence of selective INSTI therapy.
authors.affiliation: 1 Division of Infectious Diseases, Department of Medicine, Stanford University , Stanford, California.
authors.forename: Vici
authors.initials: V
authors.lastname: Varghese
authors.affiliation: 1 Division of Infectious Diseases, Department of Medicine, Stanford University , Stanford, California.|2 Department of Pathology, Stanford University , Stanford, California.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Pinsky
authors.affiliation: 3 Department of Microbiology and Immunology, Stanford University , Stanford, California.|4 Kaiser Permanente Medical Care Program-Northern California , Oakland, California.
authors.forename: Darvin S
authors.initials: DS
authors.lastname: Smith
authors.affiliation: 4 Kaiser Permanente Medical Care Program-Northern California , Oakland, California.
authors.forename: Daniel
authors.initials: D
authors.lastname: Klein
authors.affiliation: 1 Division of Infectious Diseases, Department of Medicine, Stanford University , Stanford, California.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
mesh_terms: D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D020125:Mutation, Missense; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase