Abstract
ObjectiveMutations associated with HIV drug resistance have been extensively characterized at the HIV-1 polymerase domain, but more studies have verified that mutations outside of the polymerase domain also results in resistance to antiviral drugs. In this study, mutations were identified in 354 patients experiencing antiretroviral therapy (ART) failure and in 97 naïve-therapy patients. Mutations whose impact on antiviral drugs was unknown were verified by phenotypic testing.MethodsPol sequences of HIV subtype B′ obtained from patients experiencing ART failure and from naïve-therapy patients were analyzed for mutations distinct between two groups. Mutations that occurred at a significantly higher frequency in the ART failure than the naïve-therapy group were submitted to the Stanford HIV Drug Resistance Database (SHDB) to analyze the correlation between HIV mutations and drug resistance. For mutations whose impact on the antiviral drug response is unknown, the site-directed mutagenesis approach was applied to construct plasmids containing the screened mutations. 50% inhibitory concentration (IC50) to AZT, EFV and NVP was measured to determine the response of the genetically constructed viruses to antiviral drugs.Results7 mutations at 6 positions of the RT region, D123E, V292I, K366R, T369A, T369V, A371V and I375V, occurred more frequently in the ART failure group than the naïve-therapy group. Phenotypic characterization of these HIV mutants revealed that constructed viruses with mutations A371V and T369V exhibited dual resistance to AZT and EFV respectively, whereas the other 5 mutations showed weak resistance. Although the impact of the other six mutations on response to NVP was minimal, mutation T369V could enhance resistance to NVP.ConclusionsThis study demonstrated that mutations at the RT C-terminal in subtype B′ could result in resistance to RT inhibitors if the mutations occurred alone, but that some mutations could promote susceptibility to antiviral drugs.
Highlights
Over 138 mutations in HIV-1 that are associated with drug resistance have been found since the first drug mutation was identified in 1989 [1]. 34 of these mutations at 15 positions associate with nucleoside reverse transcriptase inhibitors (NRTIs) and 19 mutations at 10 positions associate with non-nucleoside reverse transcriptase inhibitors (NNRTIs) at the reverse transcriptase (RT) region
The drug resistance mutations of HIV-1 usually occur at the polymerase domain, recent studies have verified that mutations at the RT C-terminal domains results in resistance to RT inhibitors [4,5,6,7,8,9,10,11,12,13,14,15]
Research have shown that the subtype B9 epidemics among infected paid blood donors (PBD) and heterosexuals in inland China most likely originated from a single founding subtype B9 strain that had been circulating among IDUs in Yunnan province [21]
Summary
Over 138 mutations in HIV-1 that are associated with drug resistance have been found since the first drug mutation was identified in 1989 [1]. 34 of these mutations at 15 positions associate with nucleoside reverse transcriptase inhibitors (NRTIs) and 19 mutations at 10 positions associate with non-nucleoside reverse transcriptase inhibitors (NNRTIs) at the reverse transcriptase (RT) region. Research have shown that the subtype B9 epidemics among infected paid blood donors (PBD) and heterosexuals in inland China most likely originated from a single founding subtype B9 strain that had been circulating among IDUs in Yunnan province [21]. As one of the popular strains in China, the HIV-1 subtype B9 has been prevalent for a long time since it was introduced to China, and potentially experienced selective pressure under antiviral drugs since 2003. These reasons make it worthwhile to investigate whether novel mutations associated with drug resistance would exist in subtype B9. This paper aimed to screen and identify novel mutations associated with drug resistance in subtype B9 by identifying mutations at the pol region of HIV-1 that are present in the ART failure group but not in the naıve-therapy group
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