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.
Highlights
In the vast majority of cases, HIV-1 transmission occurs at mucosal sites
We have previously demonstrated that the peptide P1 (a.a. 649–683) derived from the membrane proximal region (MPR) of gp41 acts as a galactose-specific lectin in binding to galactosyl ceramide (GalCer), the HIV-1 mucosal receptor expressed on both epithelial and dendritic cells [2,4,5]
As P1 and P5 comprise a larger portion of the MPR and were crucial for HIV entry in mucosa, we have evaluated in the present study their antiviral activity against HIV-1mediated fusion and infection in comparison with T20, which comprises a more restricted region of the MPR
Summary
In the vast majority of cases, HIV-1 transmission occurs at mucosal sites. The initial target cells for HIV-1 at mucosal sites include epithelial cells (CD4-negative) in simple monostratified mucosa (rectum, gastrointestinal tract, endo-cervix) and dendritic cells in pluristratified mucosa (vagina, exo-cervix, foreskin). We have previously demonstrated that the peptide P1 (a.a. 649–683) derived from the membrane proximal region (MPR) of gp acts as a galactose-specific lectin in binding to GalCer, the HIV-1 mucosal receptor expressed on both epithelial and dendritic cells [2,4,5]. In this case, HIV-1 neither fuses with nor infects target cells. Upon binding to CD4 and the co-receptor CCR5/CXCR4, gp120 undergoes serial conformational changes that allow the insertion of the gp fusion peptide into the target cell membrane and formation of the pre-hairpin structure. The P7 peptide contains the transmembrane region (TM) and part of the C-terminal tail, the latter including sequences reported to be the target of neutralizing antibodies [24,25]
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