title: Impact of Y181C and/or H221Y mutation patterns of HIV-1 reverse transcriptase on phenotypic resistance to available non-nucleoside and nucleoside inhibitors in China.
abstract: BACKGROUND
  The aim of this study was to investigate the role of K101Q, Y181C and H221Y emerging in HIV-1 reverse transcriptase with different mutations patterns in phenotypic susceptibility to currently available NNRTIs (nevirapine NVP, efavirenz EFV) and NRTIs (zidovudine AZT, lamivudine 3TC, stavudine d4T) in China.
  
  
  METHODS
  Phenotype testing of currently available NNRTIs (NVP, EFV) and NRTIs (AZT, 3TC, d4T) was performed on TZM-b1 cells using recombined virus strains. P ≤ 0.05 was defined significant considering the change of 50% inhibitory drug concentration (IC50) compared with the reference, while P ≤ 0.01 was considered to be statistically significant considering multiple comparisons.
  
  
  RESULTS
  Triple-mutation K101Q/Y181C/H221Y and double-mutation K101Q/Y181C resulted in significant increase in NVP resistance (1253.9-fold and 986.4-fold), while only K101Q/Y181C/H221Y brought a 5.00-fold significant increase in EFV resistance. Remarkably, K101Q/H221Y was hypersusceptible to EFV (FC = 0.04), but was significantly resistant to the three NRTIs. Then, the interaction analysis suggested the interaction was not significant to NVP (F = 0.77, P = 0.4061) but significant to EFV and other three NRTIs.
  
  
  CONCLUSIONS
  Copresence of mutations reported to be associated with NNRTIs confers significant increase to NVP resistance. Interestingly, some may increase the susceptibility to EFV. Certainly, the double mutation (K101Q/H221Y) also changes the susceptibility of viruses to NRTIs. Interaction between two different sites makes resistance more complex.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Hanping
authors.initials: H
authors.lastname: Li
authors.forename: Daomin
authors.initials: D
authors.lastname: Zhuang
authors.forename: Liyan
authors.initials: L
authors.lastname: Jiao
authors.forename: Siyang
authors.initials: S
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Gui
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of AIDS Research, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dongda Street, Fengtai District, Beijing 100071, China. lijy@nic.bmi.ac.cn.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000627:therapeutic use; D002681:China; D003521:Cyclopropanes; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D009154:Mutation; D019829:Nevirapine / Q000627:therapeutic use; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D018119:Stavudine / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019829:Nevirapine; D018119:Stavudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C098320:efavirenz