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Journal of Virology, November 2007, p. 12145-12155, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01301-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy{triangledown}

Zandrea Ambrose,1* Sarah Palmer,1 Valerie F. Boltz,1 Mary Kearney,1 Kay Larsen,2 Patricia Polacino,2 Leon Flanary,2 Kelli Oswald,3 Michael Piatak Jr.,3 Jeremy Smedley,4 Wei Shao,1 Norbert Bischofberger,5 Frank Maldarelli,1 Jason T. Kimata,6 John W. Mellors,7 Shiu-Lok Hu,2 John M. Coffin,8 Jeffrey D. Lifson,4 and Vineet N. KewalRamani1*

HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland 21702,1 Washington National Primate Research Center, Seattle, Washington 98195,2 AIDS Vaccine Program, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702,3 Laboratory of Animal Sciences, SAIC-Frederick, Inc., National Cancer Institute, Bethesda, Maryland 20892,4 Gilead Sciences, Foster City, California 94404,5 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030,6 Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,7 Department of Molecular Biology and Microbiology, Tufts University, Boston, Massachusetts 021118

Received 14 June 2007/ Accepted 31 August 2007

Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does not clear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.

* Corresponding author. Mailing address for Vineet N. KewalRamani: National Cancer Institute, Building 535, Room 123, Frederick, MD 21702. Phone: (301) 846-1249. Fax: (301) 846-6777. E-mail: vineet{at}ncifcrf.gov. Mailing address for Zandrea Ambrose: University of Pittsburgh School of Medicine, 817B Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Phone: (412) 624-0512. Fax: (412) 648-8521. E-mail: ambrosez{at}dom.pitt.edu

{triangledown} Published ahead of print on 12 September 2007.

Journal of Virology, November 2007, p. 12145-12155, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01301-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hatziioannou, T., Ambrose, Z., Chung, N. P. Y., Piatak, M. Jr., Yuan, F., Trubey, C. M., Coalter, V., Kiser, R., Schneider, D., Smedley, J., Pung, R., Gathuka, M., Estes, J. D., Veazey, R. S., KewalRamani, V. N., Lifson, J. D., Bieniasz, P. D. (2009). A macaque model of HIV-1 infection. Proc. Natl. Acad. Sci. USA 106: 4425-4429 [Abstract] [Full Text]  


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