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Journal of Virology, November 2008, p. 10747-10755, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01827-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Minority Human Immunodeficiency Virus Type 1 Variants in Antiretroviral-Naive Persons with Reverse Transcriptase Codon 215 Revertant Mutations{triangledown} ,{dagger}

Yumi Mitsuya,1,{ddagger} Vici Varghese,1,{ddagger} Chunlin Wang,1 Tommy F. Liu,1 Susan P. Holmes,2 Prerana Jayakumar,1 Baback Gharizadeh,3 Mostafa Ronaghi,3 Daniel Klein,4 W. Jeffrey Fessel,4 and Robert W. Shafer1*

Division of Infectious Diseases, Department of Medicine,1 Department of Statistics,2 Stanford Genome Technology Center, Stanford University, Stanford, California,3 Kaiser-Permanente Medical Care Program-Northern California, Oakland, California4

Received 20 August 2007/ Accepted 31 July 2008

T215 revertant mutations such as T215C/D/E/S that evolve from the nucleoside reverse transcriptase (RT) inhibitor mutations T215Y/F have been found in about 3% of human immunodeficiency virus type 1 (HIV-1) isolates from newly diagnosed HIV-1-infected persons. We used a newly developed sequencing method—ultradeep pyrosequencing (UDPS; 454 Life Sciences)—to determine the frequency with which T215Y/F or other RT inhibitor resistance mutations could be detected as minority variants in samples from untreated persons that contain T215 revertants ("revertant" samples) compared with samples from untreated persons that lack such revertants ("control" samples). Among the 22 revertant and 29 control samples, UDPS detected a mean of 3.8 and 4.8 additional RT amino acid mutations, respectively. In 6 of 22 (27%) revertant samples and in 4 of 29 control samples (14%; P = 0.4), UDPS detected one or more RT inhibitor resistance mutations. T215Y or T215F was not detected in any of the revertant or control samples; however, 4 of 22 revertant samples had one or more T215 revertants that were detected by UDPS but not by direct PCR sequencing. The failure to detect viruses with T215Y/F in the 22 revertant samples in this study may result from the overwhelming replacement of transmitted T215Y variants by the more fit T215 revertants or from the primary transmission of a T215 revertant in a subset of persons with T215 revertants.

* Corresponding author. Mailing address: Division of Infectious Diseases, Room S-169, Stanford University Medical Center, Stanford, CA 94305. Phone: (650) 725-2946. Fax: (650) 725-2088. E-mail: rshafer{at}stanford.edu

{triangledown} Published ahead of print on 20 August 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Y.M. and V.V. contributed equally to this study.

Journal of Virology, November 2008, p. 10747-10755, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01827-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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