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Antimicrobial Agents and Chemotherapy, September 2004, p. 3483-3490, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3483-3490.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Efavirenz Therapy in Rhesus Macaques Infected with a Chimera of Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

Michael J. Hofman,1 Joanne Higgins,1 Timothy B. Matthews,1 Niels C. Pedersen,2 Chalet Tan,3 Raymond F. Schinazi,3 and Thomas W. North1,4*

Center for Comparative Medicine,1 Department of Medicine and Epidemiology,2 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California,4 Veterans Affairs Medical Center, Emory University School of Medicine, Decatur, Georgia3

Received 4 March 2004/ Returned for modification 22 April 2004/ Accepted 11 May 2004

The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5.9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.

* Corresponding author. Mailing address: Center for Comparative Medicine, University of California, Davis, Davis, CA 95616. Phone: (530) 752-3414. Fax: (530) 752-7914. E-mail: twnorth{at}ucdavis.edu.

Antimicrobial Agents and Chemotherapy, September 2004, p. 3483-3490, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3483-3490.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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