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Journal of Virology, April 2007, p. 3632-3639, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.01941-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Modest Human Immunodeficiency Virus Coreceptor Function of CXCR3 Is Strongly Enhanced by Mimicking the CXCR4 Ligand Binding Pocket in the CXCR3 Receptor{triangledown}

Sigrid Hatse,1* Dana Huskens,1 Katrien Princen,1,{dagger} Kurt Vermeire,1 Gary J. Bridger,2 Erik De Clercq,1 Mette M. Rosenkilde,3 Thue W. Schwartz,3 and Dominique Schols1

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium,1 AnorMed, Langley, British Columbia V2Y 1N5, Canada,2 The Panum Institute, DK-2200 Copenhagen, Denmark3

Received 6 September 2006/ Accepted 13 December 2006

The chemokine receptor CXCR3 can exhibit weak coreceptor function for several human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains and clinical isolates. These viruses produced microscopically visible cytopathicity in U87.CD4.CXCR3 cell cultures, whereas untransfected (CXCR3-negative) U87.CD4 cells remained uninfected. Depending on the particular virus, the coreceptor efficiency of CXCR3 was 100- to >10,000-fold lower compared to that of CXCR4. A CXCR3 variant carrying the CXCR4 binding pocket was constructed by simultaneous lysine-to-alanine and serine-to-glutamate substitutions at positions 300 and 304 of the CXCR3 receptor. This mutant receptor (CXCR3[K300A, S304E]) showed markedly enhanced HIV coreceptor function compared to the wild-type receptor (CXCR3[WT]). Moreover, the CXCR4 antagonist AMD3100 exhibited antagonistic and anti-HIV activities in U87.CD4.CXCR3[K300A, S304E] cells but not in U87.CD4.CXCR3[WT] cells.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. Phone: 32-16-337357. Fax: 011-32-16-337340. E-mail: sigrid.hatse{at}rega.kuleuven.be.

{triangledown} Published ahead of print on 24 January 2007.

{dagger} Present address: Tibotec BVBA, Mechelen, Belgium.

Journal of Virology, April 2007, p. 3632-3639, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.01941-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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