PloS one, 2012-02, Vol.7 (2), p.e31558
2012
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- Autor(en) / Beteiligte
- Titel
- Zidovudine (AZT) monotherapy selects for the A360V mutation in the connection domain of HIV-1 reverse transcriptase
- Ist Teil von
- PloS one, 2012-02, Vol.7 (2), p.e31558
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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-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. The A360V mutation in the connection domain of RT was selected in HIV-infected individuals that received AZT monotherapy and contributed to AZT resistance.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0031558Titel-ID: cdi_plos_journals_1323854572
- Format
- –
- Schlagworte
- Acquired immune deficiency syndrome, Adenosine Triphosphate - pharmacology, AIDS, Amino Acid Substitution - genetics, Anti-HIV Agents - pharmacology, Anti-HIV Agents - therapeutic use, Antiretroviral drugs, Biology, Clinical trials, Comparative analysis, Deoxyribonucleic acid, Dissociation, DNA, DNA polymerases, Drug resistance, Drug Resistance, Viral - drug effects, Drug Resistance, Viral - genetics, Genetic aspects, HIV, 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, Human immunodeficiency virus, Humans, Medical research, Medicine, Mutagenesis, Site-Directed, Mutant Proteins - metabolism, Mutation, Mutation - genetics, Phenotype, Protease inhibitors, Protein Structure, Tertiary, Recombination, Genetic - genetics, Reverse transcriptase inhibitors, Ribonuclease, Ribonuclease H, Ribonuclease H - metabolism, Ribonucleic acid, RNA, RNA, Viral - blood, RNA-directed DNA polymerase, Thymidine, Viruses, Zidovudine, Zidovudine - pharmacology, Zidovudine - therapeutic use