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Journal of Virology, June 2002, p. 6083-6092, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6083-6092.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

Koen K. A. Van Rompay,1 Tim B. Matthews,2 Joanne Higgins,2 Don R. Canfield,1 Ross P. Tarara,1 Mark A. Wainberg,3 Raymond F. Schinazi,4 Niels C. Pedersen,5 and Thomas W. North2,6*

California Regional Primate Research Center,1 Center for Comparative Medicine,2 Department of Veterinary Medicine & Epidemiology,5 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616,6 McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2,3 Emory University, VA Medical Center, Decatur, Georgia 300334

Received 30 January 2002/ Accepted 19 March 2002

Drug-resistant mutants with a methionine-to-valine substitution at position 184 of reverse transcriptase (M184V) emerged within 5 weeks of initiation of therapy in four newborn macaques infected with simian immunodeficiency virus (SIVmac251) and treated with lamivudine (3TC) or emtricitabine [(-)-FTC] (two animals per drug). Thus, this animal model mimics the rapid emergence of M184V mutants of HIV-1 during 3TC therapy of human patients. One animal of each treatment group developed fatal immunodeficiency at 12 weeks of age, which is similar to the rapid disease course seen in most untreated SIVmac251-infected infant macaques. To further evaluate the effect of the M184V mutation on viral fitness and virulence, groups of juvenile macaques were inoculated with the molecular clone SIVmac239 with either the wild-type sequence (group A [n = 5]) or the M184V sequence (SIVmac239-184V; group B [n = 5] and group C [n = 2]). The two SIVmac239-184V-infected animals of group C did not receive any drug treatment, and in both animals the virus population reverted to predominantly wild type (184M) by 8 weeks after inoculation. The other five SIVmac239-184V-infected animals (group B) were treated with (-)-FTC to prevent reversion. Although virus levels 1 week after inoculation were lower in the SIVmac239-184V-infected macaques than in the SIVmac239-infected animals, no significant differences were observed from week 2 onwards. Two animals in each group developed AIDS and were euthanized, while all other animals were clinically stable at 46 weeks of infection. These data demonstrate that the M184V mutation in SIV conferred a slightly reduced fitness but did not affect disease outcome.

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

Journal of Virology, June 2002, p. 6083-6092, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6083-6092.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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