title: Natural polymorphism S119R of HIV-1 integrase enhances primary INSTI resistance.
abstract: Integrase strand transfer inhibitors (INSTIs), which block proviral DNA integration into the host chromosome, are clinically effective against HIV-1 isolates exhibiting resistance to other classes of antiretroviral agents. Although naturally occurring amino acid variation has been less frequently observed in the integrase region, the functional constraints of this variation on primary INSTI resistance-associated mutations are not fully understood. In the present study, we focused on the S119G/R/P/T (S119X) polymorphisms, which are frequently observed in HIV-1 sequences derived from clinical specimens (naïve, n=458, 26%). The frequency of the S119X polymorphism together with Q148H/R (n=8, 63%) or N155H (n=12, 83%) was relatively high compared with that of naïve group. Our in vitro assays revealed that S119G/P/T alone exerted no effect on the susceptibility to INSTIs, whereas S119R enhanced the level of INSTI resistance induced by well-known INSTI resistance-associated mutations (Y143C, Q148H or N155H). Notably, the S119R polymorphism contributed to a significant (5.9-fold) increase in dolutegravir resistance caused by G140S/Q148H. Analysis of two cases of virological failure during raltegravir-based therapy showed that the accumulation and the rapid evolution of primary INSTI resistance-associated mutations coincided with the S119R mutation. These data highlight the role of the S119X polymorphism in INSTI resistance, and this polymorphism might be linked to the potential treatment outcome with INSTI-based therapy.
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan. Electronic address: hachiya@nnh.hosp.go.jp.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hachiya
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ode
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kito
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Urara
authors.initials: U
authors.lastname: Shigemi
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Imamura
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yokomaku
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan; Department of AIDS Research, Graduated School of Medicine Nagoya University, Nagoya, Aichi 460-0001, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwatani
authors.affiliation: Department of Infectious Disease and Immunology, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan; Department of AIDS Research, Graduated School of Medicine Nagoya University, Nagoya, Aichi 460-0001, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sugiura
mesh_terms: D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011110:Polymorphism, Genetic; D011728:Pyridones; D000068898:Raltegravir Potassium / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014771:Virion; D000099226:Dolutegravir
chemical_list: D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: Deep sequencing; Drug resistance; HIV-1; Integrase strand transfer inhibitor; Polymorphism