Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

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Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors.

Matthew J. Gonzales, Thomas D. Wu, Jonathan Taylor, Ilana Belitskaya, Rami Kantor, Dennis Israelski, Sunwen Chou, Andrew R. Zolopa, W. Jeffrey Fessel, and Robert W. Shafer

ABSTRACT

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 patients receiving multiple NRTIs.
Design: 1,210 subtype B RT sequences from 1,124 individuals with known antiretroviral therapy were analyzed. 569 sequences were previously published; 641 sequences were performed at the Stanford University Hospital.
Methods: Chi-square tests and logistic regression were done to identify associations between mutations and number of NRTIs received. Correlation studies and principal components analysis were done to identify mutational clusters. The Benjamini-Hochberg procedure with false discovery rates of 0.01 and 0.05 was used to correct for multiple comparisons.
Results: Mutations at 26 positions were significantly associated with NRTI therapy including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and 9 previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). All 9 previously unreported mutations correlated linearly with the number of NRTIs. Positions 20, 39, and 43 were polymorphic (1%-4% prevalence in untreated persons); positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons. NRTI-associated mutations clustered into three categories: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 203, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228, or were unclustered (positions 20, 39, 74, 184, 221). No new NNRTI-associated mutations were observed. The 9 previously unreported mutations usually occurred in isolates with known drug-resistance mutations (777/817 instances, 95%).
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 fit into one of three clusters, although several mutations (e.g. M184V) occur in multiple mutational contexts.


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