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Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5

Genes & Immunity volume 6, pages 609–619 (2005)Cite this article

Abstract

CCR5 is one of the primary coreceptors for Env-mediated fusion between cells and human immunodeficiency virus type 1 (HIV-1). Analyses of CCR5 variants in cohorts of HIV-1 high-risk individuals led to the identification of multiple single amino-acid substitutions, which may have functional consequences. This study focused on eight naturally occurring allelic variants located between amino-acid residues 60 and 334 of CCR5. All studied allelic variants were highly expressed on the cell surface of HEK-293 cells and permissive for HIV-1 infection. Variant G301V showed 3.5-fold increase in 50% effective concentration (EC50) for CCL4 (MIP 1beta) in a competitive binding assay. There was also a significant reduction in CCL5 (RANTES) EC50 for the R223Q, A335V and Y339F variants. The most unexpected functional abnormality was exhibited by the R60S variant that exhibited a loss of ligand-induced desensitization in chemotaxis assays, but showed normal CCL4 and CCL5 binding avidity. This mutation is located in the first intracellular loop, a domain that has not previously been shown to be involved in receptor desensitization. In conclusion, our results support earlier studies showing that these naturally occurring point mutations do not limit HIV-1 infection, and indicated that single amino-acid changes can have unexpected functional consequences.

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Acknowledgements

We thank Clay Osterling, Carol Lockman-Smith of Southern Research Institute, Frederick and Doug Halverson of SAIC Frederick for technical support. Dr JJ Oppenheim has provided essential review and commentary, improving this report.

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Author notes

  1. K Wigmore

    Present address: Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics and Immunology, Ontario Cancer Institute, Canada

  2. J A Turpin

    Present address: National Institute of Allergy and Infectious Disease, Bethesda, MD, USA

Authors and Affiliations

  1. Basic Research Program, SAIC Frederick, Bethesda, MD, USA

    H-F Dong, K Wigmore & M N Carrington

  2. National Cancer Institute (NCI) Center for Cancer Research (CCR) Laboratory of Genomic Diversity, Bethesda, MD, USA

    M Dean

  3. Southern Research Institute, Bethesda, MD, USA

    J A Turpin

  4. NCI/CCR/Laboratory of Molecular Immunoregulation, NCI-Frederick, Frederick, MD, USA

    O M Z Howard

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  1. H-F Dong
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Correspondence to O M Z Howard.

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This project has been funded in whole or in part with Federal funds from the National Cancer Institute, under Contract No. N01-CO-12400.

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Dong, HF., Wigmore, K., Carrington, M. et al. Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5. Genes Immun 6, 609–619 (2005). https://doi.org/10.1038/sj.gene.6364247

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