title: Rilpivirine resistance mutation E138K in HIV-1 reverse transcriptase predisposed by prevalent polymorphic mutations.
abstract: Rilpivirine is listed as a recommended or alternative key drug in the current ART guidelines. E138K in HIV-1 reverse transcriptase (RT) is a primary mutation in resistance to rilpivirine, although in vitro experiments showed it confers only <3-fold resistance. An unidentified mechanism could amplify resistance to rilpivirine conferred by E138K.
  
  
  
  The objective of this study was to reveal the mechanism amplifying rilpivirine resistance conferred by E138K.
  
  
  
  HIV-1 RT sequences were compared in patients who failed rilpivirine-containing ART virologically. The effects of mutations commonly identified with E138K on rilpivirine susceptibility were analysed by using recombinant HIV-1 variants.
  
  
  
  Rilpivirine-containing ART was introduced in 162 HIV-1-infected patients at the outpatient clinic of the AIDS Clinical Center (National Center for Global Health and Medicine, Tokyo, Japan) between May 2012 and June 2015. Virological treatment failure occurred in six of these patients. E138K emerged in three patients while other rilpivirine resistance mutations emerged in the other three patients. I135T/L were identified in only three patients with E138K and existed before the introduction of rilpivirine-containing ART. Analysis of recombinant HIV-1 variants indicated that E138K conferred low-level rilpivirine resistance and that coexistence of I135T/L with E138K amplified the resistance.
  
  
  
  I135T/L, escape mutations from HLA-B*51/52-restricted cytotoxic T lymphocytes, which are prevalent in Japan, may predispose HIV-1 to harbour E138K upon failure of rilpivirine-containing ART. The mutation patterns of drug resistance may vary due to baseline polymorphic mutations.
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Tsunefusa
authors.initials: T
authors.lastname: Hayashida
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hachiya
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ode
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishijima
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sugiura
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan Center for AIDS Research, Kumamoto University, Kumamoto, Japan higatana@acc.ncgm.go.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D011110:Polymorphism, Genetic; D015995:Prevalence; D000068696:Rilpivirine / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine