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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).

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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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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brehm, JH
Scott, Yyas23@pitt.eduYAS23
Koontz, DLzonarich@pitt.eduZONARICH
Perry, S
Hammer, S
Katzenstein, D
Mellors, JWjwm1@pitt.eduJWM1
Sluis-Cremer, Nnps2@pitt.eduNPS2
Contributors:
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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: Graduate 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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