HIV-1 reverse transcriptase thumb subdomain polymorphisms associated with virological failure to nucleoside drug combinations.
OBJECTIVE
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. chi(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.
Garriga
César
C
Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Pérez-Elías
María Jesús
MJ
Delgado
Rafael
R
Ruiz
Lidia
L
Pérez-Alvarez
Lucía
L
Pumarola
Tomàs
T
López-Lirola
Ana
A
González-García
Juan
J
Menéndez-Arias
Luis
L
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
D019380:Anti-HIV Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase