Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics.
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.
Nakahara
Koichiro
K
Virology, Shionogi Research Laboratories, Shionogi & Co., Ltd., 2-5-1, Mishima, Settsu-shi, Osaka 566-0022, Japan.
Wakasa-Morimoto
Chiaki
C
Kobayashi
Masanori
M
Miki
Shigeru
S
Noshi
Takeshi
T
Seki
Takahiro
T
Kanamori-Koyama
Mikiko
M
Kawauchi
Shinobu
S
Suyama
Akemi
A
Fujishita
Toshio
T
Yoshinaga
Tomokazu
T
Garvey
Edward P
EP
Johns
Brian A
BA
Foster
Scott A
SA
Underwood
Mark R
MR
Sato
Akihiko
A
Fujiwara
Tamio
T
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*
D019380:Anti-HIV Agents; D005663:Furans; C451733:S 1360; D014230:Triazoles; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1