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Journal of Virology, November 2004, p. 11807-11815, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11807-11815.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Coevolution of RANTES Sensitivity and Mode of CCR5 Receptor Use by Human Immunodeficiency Virus Type 1 of the R5 Phenotype

Ingrid Karlsson,^1* Liselotte Antonsson,² Yu Shi,³ Monica Öberg,¹ Anders Karlsson,⁴ Jan Albert,³ Björn Olde,² Christer Owman,² Marianne Jansson,¹ and Eva Maria Fenyö¹

Division of Virology, Department of Medical Microbiology, Dermatology and Infection,¹ Division of Molecular Neurobiology, Department of Physiological Sciences, Lund University, Lund,² Swedish Institute for Infectious Disease Control and Microbiology and Tumorbiology Center, Karolinska Institute,³ Venhälsan, South Hospital, Stockholm, Sweden⁴

Received 24 March 2004/ Accepted 24 June 2004

The evolution of human immunodeficiency virus type 1 (HIV-1) coreceptor use has been described as the acquisition of CXCR4 use linked to accelerated disease progression. However, CXCR4-using virus can be isolated only from approximately one-half of individuals with progressive HIV-1 disease. The other half continue to yield only CCR5-using viruses (R5 phenotype) throughout the course of disease. In the present work, the use of receptor chimeras between CCR5 and CXCR4 allowed us to study the evolution of HIV-1 with the R5 phenotype, which was not revealed by studies of wild-type coreceptor use. All together, 246 isolates (173 with the R5 phenotype) from 31 individuals were tested for their ability to infect cells through receptor chimeras. R5^narrow virus was able to use only wild-type CCR5, whereas R5^broad(1) to R5^broad(3) viruses were able to use one to three chimeric receptors, respectively. Broad use of chimeric receptors was interpreted as an increased flexibility in the mode of receptor use. R5^broad isolates showed higher infectivity in cells expressing wild-type CCR5 than R5^narrow isolates. Also, the increased flexibility of R5^broad isolates was concomitant with a lower sensitivity to inhibition by the CC chemokine RANTES. Our results indicate a close relationship between HIV-1 phenotypic changes and the pathogenic process, since the mode and efficiency of CCR5 use as well as the decrease in the RANTES sensitivities of isolated viruses are significantly correlated with CD4⁺-T-cell decline in a patient. One possible explanation is that ligand competition at the CCR5 receptor or changed CCR5 availability may shape the outcome of HIV-1 infection.

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* Corresponding author. Mailing address: Division of Virology, Department of Medical Microbiology, Dermatology and Infection, Lund University, Sölvegatan 23, 223 62 Lund, Sweden. Phone: 46 46 173271. Fax: 4646 176033. E-mail: Ingrid.Karlsson{at}mmb.lu.se.

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Journal of Virology, November 2004, p. 11807-11815, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11807-11815.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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