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Journal of Virology, December 2008, p. 11758-11766, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01141-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Evolution of CCR5 Use before and during Coreceptor Switching{triangledown} ,{dagger}

Mia Coetzer,1 Rebecca Nedellec,1 Janelle Salkowitz,1,{ddagger} Sherry McLaughlin,2 Yi Liu,2 Laura Heath,2 James I. Mullins,2 and Donald E. Mosier1*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,1 Department of Microbiology, The University of Washington School of Medicine, Seattle, Washington 981952

Received 30 May 2008/ Accepted 15 September 2008

The envelope gene (env) of human immunodeficiency virus type 1 (HIV-1) undergoes rapid divergence from the transmitted sequence and increasing diversification during the prolonged course of chronic infection in humans. In about half of infected individuals or more, env evolution leads to expansion of the use of entry coreceptor from CCR5 alone to CCR5 and CXCR4. The stochastic nature of this coreceptor switch is not well explained by host selective forces that should be relatively constant between infected individuals. Moreover, differences in the incidence of coreceptor switching among different HIV-1 subtypes suggest that properties of the evolving virus population drive the switch. We evaluated the functional properties of sequential env clones from a patient with evidence of coreceptor switching at 5.67 years of infection. We found an abrupt decline in the ability of viruses to use CCR5 for entry at this time, manifested by a 1- to 2-log increase in susceptibility to CCR5 inhibitors and a reduced ability to infect cell lines with low CCR5 expression. There was an abnormally rapid 5.4% divergence in env sequences from 4.10 to 5.76 years of infection, with the V3 and V4/V5 regions showing the greatest divergence and evidence of positive selection. These observations suggest that a decline in the fitness of R5 virus populations may be one driving force that permits the emergence of R5X4 variants.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037. Phone: (858) 784-9121. Fax: (858) 784-9190. E-mail: dmosier{at}scripps.edu

{triangledown} Published ahead of print on 24 September 2008.

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

{ddagger} Present address: Department of Biological Sciences, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79968.

Journal of Virology, December 2008, p. 11758-11766, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01141-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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