Zidovudine (AZT) monotherapy selects for the A360V mutation in the connection domain of HIV-1 reverse transcriptase.

PloS One
Jessica H BrehmAIDS Clinical Trials Group Study 175 Protocol Team

Abstract

We previously demonstrated in vitro that zidovudine (AZT) selects for A371V in the connection domain and Q509L in ribonuclease H (RNase H) domain of HIV-1 reverse transcriptase (RT) which, together with the thymidine analog mutations D67N, K70R and T215F, confer greater than 100-fold AZT resistance. The goal of the current study was to determine whether AZT monotherapy in HIV-1 infected patients also selects the A371V, Q509L or other mutations in the C-terminal domains of HIV-1 RT. Full-length RT sequences in plasma obtained pre- and post-therapy were compared in 23 participants who received AZT monotherapy from the AIDS Clinical Trials Group study 175. Five of the 23 participants reached a primary study endpoint. Mutations significantly associated with AZT monotherapy included K70R (p = 0.003) and T215Y (p = 0.013) in the polymerase domain of HIV-1 RT, and A360V (p = 0.041) in the connection domain of HIV-1 RT. HIV-1 drug susceptibility assays demonstrated that A360V, either alone or in combination with thymidine analog mutations, decreased AZT susceptibility in recombinant viruses containing participant-derived full-length RT sequences or site-directed mutant RT. Biochemical studies revealed that A360V enhances the AZT-monoph...Continue Reading

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Citations

May 24, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jessica H BrehmUNKNOWN CIPRA-SA Project 1 Study Team
Nov 12, 2013·Antiviral Research·Jeffrey D MeteerNicolas Sluis-Cremer

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Methods Mentioned

BETA
Assay
genotyping

Clinical Trials Mentioned

NCT00000625

Software Mentioned

REGA HIV - 1 Subtyping Tool
Sequencher

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