Mutations in the connection and RNase H C-terminal reverse transcriptase (RT) domains of HIV-1 have been shown to impact drug resistance to RT inhibitors. However, their impact in the context of non-B subtypes has been poorly assessed. This study aimed to characterize resistance-related mutations in the C-terminal portions of RT in treatment-failing patients from southern Brazil, a region with endemic HIV-1 subtype C (HIV-1C). Viral RNA was isolated and reverse transcribed from 280 infected subjects, and genomic regions were analyzed by polymerase chain reaction, DNA sequencing, and phylogenetic analysis. Two novel mutations, M357R and E529D, were evidenced in Brazilian HIV-1C strains from treatment-failing patients. In global viral isolates of subjects on treatment, M357R was selected in HIV-1C and CRF01_AE and E529D was selected in HIV-1 subtype B (HIV-1B). While most C-terminal RT mutations described for HIV-1B also occur in HIV-1C, this work pinpointed novel mutations that display subtype-specific predominance or occurrence.
Highly active antiretroviral therapy (HAART) contributed to the improvement in the life expectancy of HIVinfected patients. However, the emergence of drug-resistant mutations (DRM) is a major viral factor impacting therapeutic failure. Differences in DRM can occur among HIV-1 subtypes. We evaluate the kinetics of the selection of resistance mutations in vitro analyzing two chimeric clones that contain the reverse transcriptases of subtypes B or C (RTB¢ and RTC¢) in cells treated with increasing concentrations of tenofovir disoproxil fumarate (TDF) and didanosine (ddI). The mutation K65R is selected more quickly in RTC¢ than in RTB¢ viruses with TDF and ddI, and additional mutations (positions 45, 62, and 68) were selected after K65R fixation. Other primary mutations (M184V and Q151M) were selected with ddI treatment in conjunction with K65R only in RTC¢ viruses. Both patterns, M184V + K65R and Q151M + K65R, have a significant impact on NRTI resistance. Our data suggest that selection of TDF and ddI DRMs can occur earlier in subtype C HIV in patients when compared to subtype B.
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