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J. Biol. Chem., Vol. 281, Issue 39, 28529-28535, September 29, 2006

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A Tyrosine-sulfated Peptide Derived from the Heavy-chain CDR3 Region of an HIV-1-neutralizing Antibody Binds gp120 and Inhibits HIV-1 Infection^*

Tatyana Dorfman, Michael J. Moore, Alexander C. Guth, Hyeryun Choe, and Michael Farzan¹

From the Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772 and the Pulmonary Division, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Sulfated tyrosines at the amino terminus of the principal HIV-1 coreceptor CCR5 play a critical role in its ability to bind the HIV-1 envelope glycoprotein gp120 and mediate HIV-1 entry. Human antibodies that recognize the CCR5-binding region of gp120 are also modified by tyrosine sulfation, which is necessary for their ability to neutralize HIV-1. Here we demonstrate that a sulfated peptide derived from the CDR3 region of one of these antibodies, E51, can efficiently bind gp120. Association of this peptide, pE51, with gp120 requires tyrosine sulfation and is enhanced by, but not dependent on, CD4. Alteration of any of four pE51 tyrosines, or alteration of gp120 residues 420, 421, or 422, critical for association with CCR5, prevents gp120 association with pE51. pE51 neutralizes HIV-1 more effectively than peptides based on the CCR5 amino terminus and may be useful as a fusion partner with other protein inhibitors of HIV-1 entry. Our data provide further insight into the association of the CCR5 amino terminus with gp120, show that a conserved, sulfate-binding region of gp120 is accessible to inhibitors in the absence of CD4, and suggest that soluble mimetics of CCR5 can be more effective than previously appreciated.

Received for publication, March 23, 2006 , and in revised form, July 12, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, 1 Pine Hill Dr., Southborough, MA 01772-9102. Tel.: 508-624-8109; Fax: 508-786-3317; E-mail: farzan{at}hms.harvard.edu.

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