Peptide P5 (residues 628–683), comprising the entire membrane proximal region of HIV-1 gp41 and its calcium-binding site, is a potent inhibitor of HIV-1 infection

doi:10.1186/1742-4690-5-93

Retrovirology

Volume 5

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Tudor D
Alfsen A
Labrosse B
Clavel F
Bomsel M

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Bomsel M
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Peptide P5 (residues 628–683), comprising the entire membrane proximal region of HIV-1 gp41 and its calcium-binding site, is a potent inhibitor of HIV-1 infection

Huifeng Yu¹^,2 , Daniela Tudor¹^,2 , Annette Alfsen¹^,2 , Beatrice Labrosse³^,4 , François Clavel³^,4 and Morgane Bomsel¹^,2

¹Entrée Muqueuse du VIH et Immunité Muqueuse, (Mucosal Entry of HIV-1 and Mucosal Immunity), Departement de Biologie Cellulaire, (Cell Biology Department), Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 22 rue Mechain, 75014 Paris, France

²Inserm, U567, Paris, France

³Inserm U552 Hopital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018 Paris, France

⁴Université Paris Diderot, Paris, France

author email corresponding author email

Retrovirology 2008, 5:93doi:10.1186/1742-4690-5-93


Published:	16 October 2008

Abstract

The membrane proximal region (MPR) of the transmembrane subunit, gp41, of the HIV envelope glycoprotein plays a critical role in HIV-1 infection of CD4⁺ target cells and CD4-independent mucosal entry. It contains continuous epitopes recognized by neutralizing IgG antibodies 2F5, 4E10 and Z13, and is therefore considered to be a promising target for vaccine design. Moreover, some MPR-derived peptides, such as T20 (enfuvirtide), are in clinical use as HIV-1 inhibitors. We have shown that an extended MPR peptide, P5, harbouring the lectin-like domain of gp41 and a calcium-binding site, is implicated in the interaction of HIV with its mucosal receptor. We now investigate the potential antiviral activities of P5 and other such long MPR-derived peptides. Structural studies of gp41 MPR-derived peptides using circular dichroism showed that the peptides P5 (a.a.628–683), P1 (a.a.648–683), P5L (a.a.613–683) and P7 (a.a.613–746) displayed a well-defined α-helical structure. Peptides P5 inhibited HIV-1 envelope mediated cell-cell fusion and infection of peripheral blood mononuclear cells by both X4- and R5-tropic HIV-1 strains, whereas peptides P5 mutated in the calcium binding site or P1 lacked antiviral activity, when P5L blocked cell fusion in contrast to P7. Strikingly, P5 inhibited CD4-dependent infection by T20-resistant R5-tropic HIV-1 variants. Cell-cell fusion studies indicated that the anti-HIV-1 activity of P5, unlike T20, could not be abrogated in the presence of the N-terminal leucine zipper domain (LZ). These results suggested that P5 could serve as a potent fusion inhibitor.