Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors.
OBJECTIVE
To characterize reverse transcriptase (RT) mutations by their association with extent of nucleoside RT inhibitor (NRTI) therapy. To identify mutational clusters in RT sequences from persons receiving multiple NRTI.


METHODS
A total of 1210 RT sequences from persons with known antiretroviral therapy were analyzed: 641 new sequences were performed at Stanford University Hospital; 569 were previously published.


METHODS
Chi-square tests and logistic regression were done to identify associations between mutations and NRTI therapy. Correlation studies were done to identify mutational clusters. The Benjamini-Hochberg procedure was used to correct for multiple comparisons.


RESULTS
Mutations at 26 positions were significantly associated with NRTI including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NRTI; 777 out of 817 (95%) instances occurred with known drug resistance mutations. Positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons; positions 20, 39, and 43 were polymorphic. Most NRTI-associated mutations clustered into three groups: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228.


CONCLUSIONS
Mutations at nine previously unreported positions are associated with NRTI therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts.
Gonzales
Matthew J
MJ
Division of Infectious Diseases, Department of Medicine, Stanford University, CA, USA.
Wu
Thomas D
TD
Taylor
Jonathan
J
Belitskaya
Ilana
I
Kantor
Rami
R
Israelski
Dennis
D
Chou
Sunwen
S
Zolopa
Andrew R
AR
Fessel
W Jeffrey
WJ
Shafer
Robert W
RW
D001483:Base Sequence; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008969:Molecular Sequence Data; D009154:Mutation; D025341:Principal Component Analysis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase