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Journal of Virology, November 2000, p. 10269-10273, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Reduced Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) from Patients with Primary HIV Infection to Nonnucleoside Reverse Transcriptase Inhibitors Is Associated with Variation at Novel Amino Acid Sites

Andrew J. Leigh Brown,1,* Heather M. Precious,1 Jeannette M. Whitcomb,2 Joseph K. Wong,3 Marlynne Quigg,1 Wei Huang,2 Eric S. Daar,4 Richard T. D'Aquila,5 Philip H. Keiser,6 Elizabeth Connick,7 Nicholas S. Hellmann,2 Christos J. Petropoulos,2 Douglas D. Richman,3 and Susan J. Little3

Centre for HIV Research, Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, Scotland1; Department of Medicine, University of California, San Diego, and San Diego Veterans Affairs Medical Center, La Jolla,3 ViroLogic, Inc., South San Francisco,2 and Cedars-Sinai Burns & Allen Research Institute and University of California, Los Angeles, Los Angeles,4 California; Massachusetts General Hospital, Boston, Massachusetts5; University of Texas Southwestern Medical Center, Dallas, Texas6; and University of Colorado Health Sciences Center and Department of Veterans Affairs Medical Center, Denver, Colorado7

Received 5 June 2000/Accepted 19 August 2000

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infection have been found to harbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5- and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

* Corresponding author. Mailing address: Department of Pathology, UCSD Treatment Center, 150 W. Washington St., San Diego, CA 92103. Phone: (619) 543-8080. Fax: (619) 298-0177. E-mail: A.Leigh-Brown{at}ed.ac.uk.

Journal of Virology, November 2000, p. 10269-10273, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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