Mutations in the connection domain of HIV-1 reverse transcriptase increase 3'-azido-3'-deoxythymidine resistance

We previously proposed that a balance between nucleotide excision and template RNA degradation plays an important role in nucleoside reverse transcriptase inhibitor (NRTI) resistance. To explore the predictions of this concept, we analyzed the role of patient-derived C-terminal domains of HIV-1 reve...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-01, Vol.104 (1), p.317-322
Main Authors: Nikolenko, Galina N, Delviks-Frankenberry, Krista A, Palmer, Sarah, Maldarelli, Frank, Fivash, Matthew J. Jr, Coffin, John M, Pathak, Vinay K
Format: Article
Language:English
Subjects:
Acquired Immunodeficiency Syndrome - drug therapy
Amino Acid Sequence
Amino acid substitution
Amino acids
Anti-HIV Agents - pharmacology
Antivirals
Biological Sciences
Cell lines
Drug resistance
Drug Resistance, Viral
Genetic mutation
Genetic recombination
Genotype & phenotype
HIV 1
HIV Reverse Transcriptase - chemistry
HIV Reverse Transcriptase - genetics
Human immunodeficiency virus 1
Humans
Molecular Sequence Data
Mutation
Nucleotides
Protein Structure, Tertiary
RNA stability
Virus Replication
Viruses
Zidovudine - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:We previously proposed that a balance between nucleotide excision and template RNA degradation plays an important role in nucleoside reverse transcriptase inhibitor (NRTI) resistance. To explore the predictions of this concept, we analyzed the role of patient-derived C-terminal domains of HIV-1 reverse transcriptase (RT) in NRTI resistance. We found that when the polymerase domain contained previously described thymidine analog resistance mutations, mutations in the connection domain increased resistance to 3'-azido-3'-deoxythymidine (AZT) from 11-fold to as much as 536-fold over wild-type RT. Mutational analysis showed that amino acid substitutions E312Q, G335C/D, N348I, A360I/V, V365I, and A376S were associated strongly with the observed increase in AZT resistance; several of these mutations also decreased RT template switching, suggesting that they alter the predicted balance between nucleotide excision and template RNA degradation. These results indicate that mutations in the C-terminal domain of RT significantly enhance clinical NRTI resistance and should be considered in genotypic and phenotypic drug resistance studies.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0609642104