title: Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics.
abstract: Passage of HIV-1 in the presence of integrase inhibitors (INIs) generates resistant viruses that have mutations in the integrase region. Integrase-resistant mutations Q148K and Q148R were identified as primary mutations with the passage of HIV-1 IIIB in the presence of INIs S-1360 or S/GSK-364735, respectively. Secondary amino acid substitutions E138K or G140S were observed when passage with INI was continued. The role of these mutations was investigated with molecular clones. Relative to Q148K alone, Q148K/E138K had 2- and >6-fold increases in resistance to S-1360 and S/GSK-364735, respectively, and the double mutant had slightly better infectivity and replication kinetics. In contrast, Q148K/G140S and Q148R/E138K had nearly equivalent or slightly reduced fold resistance to the INI compared with their respective Q148 primary mutants, and had increases in infectivity and replication kinetics. Recovery of these surrogates of viral fitness coincided with the recovery of integration efficiency of viral DNA into the host cell chromosome for these double mutants. These data show that recovery of viral integration efficiency can be an important factor for the emergence and maintenance of INI-resistant mutations.
authors.affiliation: Virology, Shionogi Research Laboratories, Shionogi & Co., Ltd., 2-5-1, Mishima, Settsu-shi, Osaka 566-0022, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nakahara
authors.forename: Chiaki
authors.initials: C
authors.lastname: Wakasa-Morimoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noshi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Mikiko
authors.initials: M
authors.lastname: Kanamori-Koyama
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kawauchi
authors.forename: Akemi
authors.initials: A
authors.lastname: Suyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Fujishita
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshinaga
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Scott A
authors.initials: SA
authors.lastname: Foster
authors.forename: Mark R
authors.initials: MR
authors.lastname: Underwood
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D020125:Mutation, Missense; D014230:Triazoles / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D005663:Furans; C451733:S 1360; D014230:Triazoles; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1