title: Different Effects of Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Cytotoxic T Lymphocyte Recognition between HIV-1 Subtype B and Subtype A/E Infections.
abstract: The effect of antiretroviral drug resistance mutations on cytotoxic T lymphocyte (CTL) recognition has been analyzed in HIV-1 subtype B infections, but it remains unclear in infections by other HIV-1 subtypes that are epidemic in countries where antiretroviral drugs are not effectively used. We investigated the effect of nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI)-resistance mutations (Y181C, Y181I, and Y181V) on epitope recognition by CTLs specific for 3 different HIV-1 epitopes (HLA-A*02:01-restricted IV10, HLA-B*35:01-restricted NY9, and HLA-C*12:02-restricted KY9) in subtype B and subtype A/E infections and the accumulation of these mutations in treatment-naive Japanese and Vietnamese. These NNRTI-resistance mutations critically affected NY9-specific and KY9-specific T cell responses in the subtype B infections, whereas they showed a different effect on IV10-specific T cell responses among the subtype B-infected individuals. These mutations affected IV10-specific T cell responses but weakly affected NY9-specific T cell responses in the subtype A/E infections. The substitution at position 3 of NY9 epitope which was found in the subtype A/E virus differently influenced the peptide binding to HLA-B*35:01, suggesting that the differences in peptide binding may result in the differences in T cell recognition between the subtype B virus and A/E virus infections. The Y181C mutation was found to be accumulating in treatment-naive Vietnamese infected with the subtype A/E virus. The present study demonstrated different effects of NNRTI-resistance RT181 mutations on CTL responses between the 2 subtype infections. The Y181C mutation may influence HIV-1 control by the CTLs in Vietnam, since this mutation has been accumulating in treatment-naive Vietnamese.
  
  
  OBJECTIVE
  Antiretroviral therapy leads to the emergence of drug-resistant HIV-1, resulting in virological and clinical failures. Though HIV-1-specific CTLs play a critical role in HIV-1 infection, some of drug resistance mutations located in CTL epitopes are known to affect HIV-1-specific CTL responses. Nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance RT181 mutations are frequently observed in patients treated with NNRTIs. Such drug resistance mutations may have an influence on immune control by HIV-1-specific CTLs, especially in countries where antiretroviral drugs are not effectively used. We here investigated the effect of three NNRTI-resistance RT181 mutations on immune responses by HIV-1-specific CTLs and the recent accumulation of these mutations in treatment-naive Vietnamese infected with HIV-1 subtype A/E virus. RT181 mutations affected CTL recognition in both subtype A/E and B infections, while the RT Y181C mutation has been accumulating in treatment-naive Vietnamese. The results suggest that the Y181C mutation may influence HIV-1 control by CTLs in Vietnam.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kuse
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Mohammad Arif
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Murakoshi
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Giang Van
authors.initials: GV
authors.lastname: Tran
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chikata
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Koyanagi
authors.affiliation: National Hospital of Tropical Diseases, Dong Da District, Hanoi, Vietnam.
authors.forename: Kinh Van
authors.initials: KV
authors.lastname: Nguyen
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan masafumi@kumamoto-u.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D024882:Drug Resistance, Viral; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005838:Genotype; D015658:HIV Infections / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007564:Japan; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D020125:Mutation, Missense; D009705:Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014744:Vietnam
chemical_list: D000939:Epitopes; D050505:Mutant Proteins; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase