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J Virol, February 1998, p. 1160-1164, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Tyrosine-Rich Region in the N Terminus of CCR5 Is Important for Human Immunodeficiency Virus Type 1 Entry and Mediates an Association between gp120 and CCR5

Michael Farzan,1 Hyeryun Choe,1 Luis Vaca,1 Kathleen Martin,2 Ying Sun,1 Elizabeth Desjardins,1 Nancy Ruffing,3 Lijun Wu,1 Richard Wyatt,1 Norma Gerard,4 Craig Gerard,2,* and Joseph Sodroski1,4,*

Division of Human Retrovirology, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School,1 Perlmutter Laboratory, Children's Hospital, and Departments of Medicine and Pediatrics, Beth Israel Hospital and Harvard Medical School,2 and Department of Cancer Biology, Harvard School of Public Health,4 Boston, Massachusetts, and LeukoSite, Inc., Cambridge, Massachusetts 021423

Received 19 August 1997/Accepted 27 October 1997

Human immunodeficiency virus type 1 (HIV-1) requires the presence of specific chemokine receptors in addition to CD4 to enter target cells. The chemokine receptor CCR5 is used by the macrophage-tropic strains of HIV-1 that predominate during the asymptomatic stages of infection. Here we identify a small tyrosine-rich region of CCR5 proximal to the N-terminal cysteine that is critical for entry of macrophage-tropic and dual-tropic variants of HIV-1. HIV-1 infection of cells expressing CCR5 mutants with changes in this region was substantially reduced compared with the infection of cells bearing wild-type CCR5. Simian immunodeficiency virus (SIVmac239) entry was also ablated on a subset of these mutants but enhanced on others. These differences in virus entry were correlated with the relative ability of soluble, monomeric HIV-1 and SIVmac239 gp120 glycoproteins to bind the CCR5 mutants. These results identify a region of CCR5 that is necessary for the physical association of the gp120 envelope glycoprotein with CCR5 and for HIV-1 infection.

* Corresponding author. Mailing address for Craig Gerard: Perlmutter Laboratory, Children's Hospital, Hunnewell, 300 Longwood Ave., Boston, MA 02115. Phone: (617) 735-6174. Fax: (617) 730-0422. E-mail: gerard_c{at}a1.tch.harvard.edu. Mailing address for Joseph Sodroski: JFB 824, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3371. Fax: (617) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.




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