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J. Biol. Chem., Vol. 281, Issue 27, 18787-18792, July 7, 2006

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-Defensins Prevent HIV-1 Env-mediated Fusion by Binding gp41 and Blocking 6-Helix Bundle Formation^*

Stephen A. Gallo¹, Wei Wang¹, Satinder S. Rawat, Grace Jung, Alan J. Waring, Alexander M. Cole^¶, Hong Lu^||, Xuxia Yan^||, Norelle L. Daly^**, David J. Craik^**, Shibo Jiang^||, Robert I. Lehrer, and Robert Blumenthal²

From the Center for Cancer Research Nanobiology Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, the Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, the ^¶Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32816, the ^||Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021, and the ^**Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

Retrocyclin-1, a -defensin, protects target cells from human immunodeficiency virus, type 1 (HIV-1) by preventing viral entry. To delineate its mechanism, we conducted fusion assays between susceptible target cells and effector cells that expressed HIV-1 Env. Retrocyclin-1 (4 µM) completely blocked fusion mediated by HIV-1 Envs that used CXCR4 or CCR5 but had little effect on cell fusion mediated by HIV-2 and simian immunodeficiency virus Envs. Retrocyclin-1 inhibited HIV-1 Env-mediated fusion without impairing the lateral mobility of CD4, and it inhibited the fusion of CD4-deficient cells with cells bearing CD4-independent HIV-1 Env. Thus, it could act without cross-linking membrane proteins or inhibiting gp120-CD4 interactions. Retrocyclin-1 acted late in the HIV-1 Env fusion cascade but prior to 6-helix bundle formation. Surface plasmon resonance experiments revealed that retrocyclin bound the ectodomain of gp41 with high affinity in a glycan-independent manner and that it bound selectively to the gp41 C-terminal heptad repeat. Native-PAGE, enzyme-linked immunosorbent assay, and CD spectroscopic analyses all revealed that retrocyclin-1 prevented 6-helix bundle formation. This mode of action, although novel for an innate effector molecule, resembles the mechanism of peptidic entry inhibitors based on portions of the gp41 sequence.

Received for publication, March 15, 2006 , and in revised form, April 28, 2006.

^* This work was supported by the Intramural Research Program of the NCI, National Institutes of Health (NIH), Center for Cancer Research and by NIH Grant AI056921. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1-3, supplemental Fig. 1, and supplemental Experimental Procedures.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: CCR Nanobiology Program, NCI, Frederick, MD, 21702. Tel.: 301-846-5532; Fax: 301-846-5598; E-mail: blumen{at}helix.nih.gov.

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