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Journal of Virology, July 2002, p. 6836-6840, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6836-6840.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A Mutation in the 3' Region of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase (Y318F) Associated with Nonnucleoside Reverse Transcriptase Inhibitor Resistance

P. Richard Harrigan,^1* Mahboob Salim,^2, David K. Stammers,³ Brian Wynhoven,¹ Zabrina L. Brumme,¹ Paula McKenna,⁴ Brendan Larder,^2, and S. D. Kemp^2,

BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada,¹ Virco United Kingdom Ltd., Cambridge,² The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom,³ Virco, NV, Mechelen, Belgium⁴

Received 13 December 2001/ Accepted 11 March 2002

The Y318F substitution in the 3' region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been linked to nonnucleoside RT inhibitor (NNRTI) resistance in vitro. A systematic search of a large phenotypic-genotypic database (Virco) linked the Y318F substitution with a >10-fold decrease in NNRTI susceptibility in >85% of clinically derived isolates. There was a significant association between Y318F and use of delavirdine (P = 10^-11) and nevirapine (P = 10^-6) but not efavirenz (P = 0.3). Site-directed HIV-1 Y318F mutants in an HXB2 background displayed 42-fold-decreased susceptibility to delavirdine but <3-fold-decreased susceptibility to nevirapine or efavirenz. Combinations of Y318F with K103N, Y181C, or both resulted in decreased efavirenz susceptibility of 43-, 3.3-, and 84-fold, respectively, as well as >100- and >60-fold decreases in delavirdine and nevirapine susceptibility, respectively. These results indicate the importance of the Y318F substitution in HIV-1 drug resistance.

Present address: Visible Genetics, Cambridge, United Kingdom.

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