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Journal of Virology, March 2004, p. 2434-2444, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2434-2444.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Highly Uneven Distribution of Tenofovir-Selected Simian Immunodeficiency Virus in Different Anatomical Sites of Rhesus Macaques

Magdalena Magierowska,1,2 Flavien Bernardin,1,2 Seema Garg,3 Silvija Staprans,3 Michael D. Miller,4 Koen K. A. Van Rompay,5 and Eric L. Delwart1,2*

Department of Medicine, University of California—San Francisco,1 Blood Systems Research Institute, San Francisco,2 Gilead Sciences, Foster City,4 California Regional Primate Research Center, University of California—Davis, Davis, California,5 Vaccine Research Center, Emory University Medical Center, Atlanta, Georgia3

Received 8 August 2003/ Accepted 8 November 2003

Antiviral tenofovir monotherapy was used to determine whether drug-selected simian immunodeficiency virus (SIV) variants replaced their wild-type progenitors at the same rate in different tissues of six rhesus macaques. The relative frequencies of drug-resistant and wild-type genotypes were measured longitudinally in blood and in 23 lymphoid and nonlymphoid tissues collected at necropsy. The mutant/wild-type genotype ratio was measured using a heteroduplex tracking assay targeting tenofovir-selected SIV reverse transcriptase codons. After the initiation of tenofovir treatment in animals with high steady-state viremia levels, resistant genotypes emerged in the plasma within 1 to 8 weeks and in five of six cases reached frequencies of nearly 100% within 4 to 25 weeks. The appearance of tenofovir-resistant genotypes in peripheral blood mononuclear cell (PBMC) DNA was generally delayed by 1 to 2 weeks and in one case was completely absent. Necropsies performed 8 to 55 weeks after the initiation of tenofovir treatment showed the frequency of resistant SIV genotypes to be generally higher in tissue RNA than DNA fractions. The frequency of drug-resistant genotypes varied widely between anatomical sites, including different lymph nodes of the same animal. Except for the epidydimis, the tissues with the lowest rates of proviral replacement by tenofovir-resistant genotypes differed between animals. The highly uneven distribution of tenofovir-resistant genotypes in different tissues seen shortly after the initiation of tenofovir monotherapy may reflect differences in local antiviral drug selection pressures and/or the stochastic effect of small effective populations of drug-resistant variants randomly seeding different anatomical sites early in therapy.

* Corresponding author. Mailing address: Department of Medicine, University of California—San Francisco, San Francisco, CA 94118. Phone: (415) 923-5763. Fax: (419) 791-4220. E-mail: delwarte{at}medicine.ucsf.edu.

Journal of Virology, March 2004, p. 2434-2444, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2434-2444.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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