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Journal of Virology, March 2008, p. 2418-2426, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01596-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CCR5{Delta}32 59537-G/A Promoter Polymorphism Is Associated with Low Translational Efficiency and the Loss of CCR5{Delta}32 Protective Effects{triangledown}

Qingwen Jin,1,{dagger} Lokesh Agrawal,1 L. Meyer,2 R. Tubiana,3 Ioannis Theodorou,3 and Ghalib Alkhatib1*

Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Rm. 420, Indianapolis, Indiana 46202,1 INSERM Unité 292, Hôpital de Bicetre 78, Rue du Général Leclerc-94270 Le Kremlin Bicetre, Paris, France,2 Hôpital Pitié Salpetrière et INSERM UR543 Bâtiment CERVI, 83 Bd. de l'Hôpital, 75013 Paris, France3

Received 21 July 2007/ Accepted 13 December 2007

We have recently demonstrated that the CCR5{Delta}32 protein interacts with CCR5 and CXCR4 and down-modulates their cell surface expression. We have also reported the absence of detectable expression of the truncated CCR5{Delta}32 protein in four out of six human immunodeficiency virus-infected (HIV+) CCR5–/– individuals. To explain the defect in protein expression in these samples, we cloned and sequenced the promoter regions of the six HIV+ individuals. We have identified several polymorphisms in the CCR5{Delta}32 promoter region, but these polymorphisms were not associated with significant differences in mRNA levels. Coupled in vitro transcription/translation and polyribosome analysis demonstrated a strong association between a variant genotype designated CCR5{Delta}32 59537-A/A and a low translation efficiency. Protein analysis indicated that the peripheral blood mononuclear cells from two of the HIV+ CCR5–/– individuals carrying the CCR5{Delta}32 59537-A/A variant expressed trace amounts of CCR5{Delta}32 protein compared to the individuals carrying the CCR5{Delta}32 59537-G/G genotype. The results imply that the absence of CCR5{Delta}32 protein in two HIV+ individuals is due to a genetic defect in the translation of the protein. Together, these results highlight the importance of the CCR5{Delta}32 protein as an HIV suppressive factor and provide further insight into the mechanism of the protective effect of the CCR5{Delta}32 mutation.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Rm. 420, Indianapolis, IN 46202. Phone: (317) 278-3698. Fax: (317) 274-7592. E-mail: galkhati{at}iupui.edu

{triangledown} Published ahead of print on 19 December 2007.

{dagger} Present address: Department of Neurology, Nanjing Medical University, Jiangsu Province, China 210029.

Journal of Virology, March 2008, p. 2418-2426, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01596-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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