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Journal of Virology, May 2005, p. 6068-6077, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6068-6077.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Functional Mimicry of a Human Immunodeficiency Virus Type 1 Coreceptor by a Neutralizing Monoclonal Antibody

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,¹ Department of Pathology, Division of AIDS, Harvard Medical School,² Department of Immunology and Infectious Diseases, Harvard School of Public Health,³ Partners AIDS Research Center, Massachusetts General Hospital, Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115,⁴ Department of Pediatrics, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, Louisiana 70012⁵

Received 23 July 2004/ Accepted 21 November 2004

Interaction of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein with the primary receptor, CD4, promotes binding to a chemokine receptor, either CCR5 or CXCR4. The chemokine receptor-binding site on gp120 elicits CD4-induced (CD4i) antibodies in some HIV-1-infected individuals. Like CCR5 itself, the CD4i antibody 412d exhibits a preference for CCR5-using HIV-1 strains and utilizes sulfated tyrosines to achieve binding to gp120. Here, we show that 412d binding requires the gp120 ß19 strand and the base of the V3 loop, elements that are important for the binding of the CCR5 N terminus. Two gp120 residues in the V3 loop base determined 412d preference for CCR5-using HIV-1 strains. A chimeric molecule in which the 412d heavy-chain third complementarity-determining loop sequence replaces the CCR5 N terminus functioned as an efficient second receptor, selectively supporting the entry of CCR5-using HIV-1 strains. Sulfation of N-terminal tyrosines contributed to the function of this chimeric receptor. These results emphasize the close mimicry of the CCR5 N terminus by the gp120-interactive region of a naturally elicited CD4i antibody.

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