title: Identification of the critical sites of NNRTI-resistance in reverse transcriptase of HIV-1 CRF_BC strains.
abstract: BACKGROUND
  The polymorphisms involved in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC, the most prevalent HIV-1 strain in China, have been poorly characterized.
  
  
  RESULTS
  To reveal the drug resistance mutations, we compared the gene sequences of pol region of HIV-1 CRF_BC from 631 treatment-naïve and 363 treatment-experienced patients using the selection pressure-based method. We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that eight polymorphic mutations (W88C, K101Q, I132L, R135L, T139K/R, H221Y and L228R) in RT for treatment-experienced patients were identified, while they, except for R135L, were completely absent in those from treatment-naïve patients. The I132L and T139K/R mutants exhibited high-level resistance to DLV and NVP and moderate resistance to TMC-125 and EFV, while the K101Q and H221Y mutants exhibited an increased resistance to all four NNRTIs tested. The W88C, R135L, and L228R may be RTI-induced adaptive mutations. Y181C+K101Q mutant showed a 2.5-, 4.4-, and 4.7-fold higher resistance to TMC-125, NVP and EFV, respectively, than Y181C alone mutant, while Y181C+H221Y or K103N+H221Y mutants had significantly higher resistance to all four NNRTIs than Y181C or K103N mutants. K103N+T139K and G190A+T139K mutant induce higher resistance (2.0∼14.2-fold and 1.5∼7.2-fold, respectively) to all four NNRTIs than K103N or G190A alone mutation.
  
  
  CONCLUSIONS
  I132L and T139K/R are rare but critical mutations associated with NNRTI-resistance for some NNRTIs. K101Q, H221Y and T139K can enhance K103N/Y181C/G190A-assocated NNRTI-resistance. Monitoring these mutations will provide useful information for rational design of the NNRTI-based antiretroviral regimen for HIV-1 CRF_BC-infected patients.
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xing
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Yabo
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Lingjie
authors.initials: L
authors.lastname: Liao
authors.affiliation: Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Armstrong
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D012641:Selection, Genetic; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054302:pol Gene Products, Human Immunodeficiency Virus; D054303:HIV Reverse Transcriptase
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