Title

theta-defensins prevent HIV-1 Env-mediated fusion by binding gp41 and blocking 6-helix bundle formation

Authors

Authors

S. A. Gallo; W. Wang; S. S. Rawat; G. Jung; A. J. Waring; A. M. Cole; H. Lu; X. X. Yan; N. L. Daly; D. J. Craik; S. B. Jiang; R. I. Lehrer;R. Blumenthal

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

TRUNCATED ALPHA-DEFENSINS; ENVELOPE GLYCOPROTEIN; SYNTHETIC PEPTIDE; MONOCLONAL-ANTIBODY; POTENT INHIBITORS; ATOMIC-STRUCTURE; MEMBRANE-FUSION; CORE STRUCTURE; COILED-COIL; TYPE-1 GP41; Biochemistry & Molecular Biology

Abstract

Retrocyclin-1, a 0-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 mu M) 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.

Journal Title

Journal of Biological Chemistry

Volume

281

Issue/Number

27

Publication Date

1-1-2006

Document Type

Article

Language

English

First Page

18787

Last Page

18792

WOS Identifier

WOS:000238687300059

ISSN

0021-9258

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