Identification of the critical sites of NNRTI-resistance in reverse transcriptase of HIV-1 CRF_BC strains

• Published in: PloS one 2014-04, Vol.9 (4), p.e93804-e93804
• Main Authors: Huang, Yang, Li, Zhenpeng, Xing, Hui, Jiao, Yang, Ouyang, Yabo, Liao, Lingjie, Jiang, Shibo, Armstrong, Rebecca, Shao, Yiming, Ma, Liying
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Amino acids; Analysis; Antiretroviral agents; Antiretroviral drugs; Biology and Life Sciences; Comparative analysis; Diagnosis; Disease prevention; DNA polymerases; Drug resistance; Drug Resistance, Viral - genetics; Drug therapy; Evolution, Molecular; Gene sequencing; Health aspects; Highly active antiretroviral therapy; HIV; HIV infection; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Human immunodeficiency virus; Humans; Medicine and health sciences; Mutants; Mutation; Non-nucleoside reverse transcriptase inhibitors; Nucleoside reverse transcriptase inhibitors; Patients; pol Gene Products, Human Immunodeficiency Virus - genetics; Polymorphism, Genetic; Protease inhibitors; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Selection, Genetic; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0093804

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. 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. 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.