Zidovudine (AZT) monotherapy selects for the A360V mutation in the connection domain of HIV-1 reverse transcriptase
Brehm, JH and Scott, Y and Koontz, DL and Perry, S and Hammer, S and Katzenstein, D and Mellors, JW and Sluis-Cremer, N
(2012)
Zidovudine (AZT) monotherapy selects for the A360V mutation in the connection domain of HIV-1 reverse transcriptase.
PLoS ONE, 7 (2).
Abstract
Background: 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. Methodology/Principal Findings: 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-monophosphate excision activity of purified RT by significantly decreasing the frequency of secondary RNase H cleavage events that reduce the RNA/DNA duplex length and promote template/primer dissociation. Conclusions: The A360V mutation in the connection domain of RT was selected in HIV-infected individuals that received AZT monotherapy and contributed to AZT resistance. © 2012 Brehm et al.
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Date: |
21 February 2012 |
Date Type: |
Publication |
Journal or Publication Title: |
PLoS ONE |
Volume: |
7 |
Number: |
2 |
DOI or Unique Handle: |
10.1371/journal.pone.0031558 |
Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology School of Medicine > Infectious Diseases and Microbiology |
Refereed: |
Yes |
MeSH Headings: |
Adenosine Triphosphate--pharmacology; Amino Acid Substitution--genetics; Anti-HIV Agents--pharmacology; Anti-HIV Agents--therapeutic use; Drug Resistance, Viral--drug effects; Drug Resistance, Viral--genetics; HIV Infections--blood; HIV Infections--drug therapy; HIV Infections--virology; HIV Reverse Transcriptase--chemistry; HIV Reverse Transcriptase--genetics; HIV-1--drug effects; HIV-1--enzymology; HIV-1--genetics; Humans; Mutagenesis, Site-Directed; Mutant Proteins--metabolism; Mutation--genetics; Phenotype; Protein Structure, Tertiary; RNA, Viral--blood; Recombination, Genetic--genetics; Ribonuclease H--metabolism; Zidovudine--pharmacology; Zidovudine--therapeutic use |
Other ID: |
NLM PMC3283647 |
PubMed Central ID: |
PMC3283647 |
PubMed ID: |
22363673 |
Date Deposited: |
13 Sep 2012 18:03 |
Last Modified: |
21 Jan 2019 14:55 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/14142 |
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