JAC Advance Access published online on June 7, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp200
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Original research |
HIV-1 reverse transcriptase thumb subdomain polymorphisms associated with virological failure to nucleoside drug combinations
1 Centro de Biología Molecular ‘Severo Ochoa’, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid, Madrid, Spain 2 Departamento de Enfermedades Infecciosas, Hospital Universitario Ramón y Cajal, Madrid, Spain 3 Laboratorio de Microbiología Molecular, Servicio de Microbiología, Hospital Universitario Doce de Octubre, Madrid, Spain 4 Laboratori de Retrovirologia, Fundació irsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain 5 Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain 6 Servicio de Microbiología, Hospital Clínic, Barcelona, Spain 7 Servicio de Infecciones, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain 8 Servicio de Medicina Interna, Hospital Universitario La Paz, Madrid, Spain
Received 26 February 2009; returned 27 April 2009; revised 6 May 2009; accepted 11 May 2009
* Corresponding author. Centro de Biología Molecular ‘Severo Ochoa’ (CSIC-UAM), c/ Nicolás Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain. Tel: +34-911964494; Fax: +34-911964420; E-mail: lmenendez{at}cbm.uam.es
Objectives: The aim of this study was to identify mutations within the fingers, palm and thumb subdomains of the HIV-1 reverse transcriptase (RT) associated with therapy failure to various combinations of two nucleoside analogues.
Methods: RT nucleotide sequences of 1893 HIV-1 isolates from 1680 persons with different treatment histories (including naive and treated patients) were analysed. 
2 contingency tests were performed to detect mutations within positions 1–333 of HIV-1 RT, associated with therapy failure, and correlated mutations were identified using statistical methods.
Results: Thymidine analogue resistance mutations were strongly associated with therapy failure to all nucleoside analogue combinations analysed. Previously identified accessory mutations at positions 35, 39, 43, 90, 98, 101, 122, 178, 196, 203, 208, 221, 223 and 228 were associated with therapy failure with at least one of the drug combinations studied. Interestingly, several mutations affecting RT thumb subdomain polymorphisms were strongly associated (P < 10–3) with therapy failure to abacavir/stavudine, stavudine/didanosine and abacavir/stavudine/didanosine. Mutations A272P, K277R and V293I were more prevalent in patients failing treatment with abacavir/stavudine than in naive individuals, while mutation frequencies of T286A, V292I and to a lesser extent E291D and E297K decreased in the treated population. These effects were also detected for A272P, T286A and V292I, when analysing didanosine/stavudine therapy failure, although statistical significance was higher for T286A.
Conclusions: RT thumb subdomain polymorphisms are strongly associated with therapy failure to nucleoside analogues. Based on their structural location, we suggest a role for those residues in controlling the balance between RNase H degradation and nucleotide excision during DNA polymerization.
Key Words: HIV , resistance , stavudine , abacavir
Present address: Epidemiología del VIH/SIDA, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, c/ Sinesio Delgado 6, 28029 Madrid, Spain.
Participating hospitals and personnel staff of the Spanish Group for the Study of Antiretroviral Drug Resistance are listed in the Acknowledgements section.