1887

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Volume 88, Issue 2

An antibody that blocks human T-cell leukemia virus type 1 six-helix-bundle formation identified by a novel assay for inhibitors of envelope function Free

Abstract

Fusion of the viral and cellular membranes is a critical step in the infection of cells by the human T-cell leukemia virus type 1 (HTLV-1) and this process is catalysed by the viral envelope glycoproteins. During fusion, the transmembrane glycoprotein (TM) is thought to undergo a transition from a rod-like pre-hairpin conformation that is stabilized by a trimeric coiled coil to a more compact six-helix-bundle or trimer-of-hairpins structure. Importantly, synthetic peptides that interfere with the conformational changes of TM are potent inhibitors of membrane fusion and HTLV-1 entry, suggesting that the pre-hairpin motif is a valid target for antiviral therapy. Here, a stable, trimeric TM derivative that mimics the coiled-coil structure of fusion-active TM has been used to develop a plate-based assay to identify reagents that interfere with the formation of the six-helix bundle. The assay discriminates effectively between strong, weak and inactive peptide inhibitors of membrane fusion and has been used to identify a monoclonal antibody (mAb) that disrupts six-helix-bundle formation efficiently . The mAb is reactive with the C-helical region of TM, indicating that this region of TM is immunogenic. However, the mAb failed to neutralize HTLV-1 envelope-mediated membrane fusion, suggesting that, on native viral envelope, the epitope recognized by the mAb is obscured during fusion. This novel mAb will be of value in the immunological characterization of fusion-active structures of HTLV-1 TM. Moreover, the assay developed here will aid the search for therapeutic antibodies, peptides and small-molecule inhibitors targeting envelope and the HTLV-1 entry process.

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2007-02-01
2024-05-10
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An antibody that blocks human T-cell leukemia virus type 1 six-helix-bundle formation in vitro identified by a novel assay for inhibitors of envelope function
J. Gen. Virol. 88, 660 (2007); https://doi.org/10.1099/vir.0.82390-0
/content/journal/jgv/10.1099/vir.0.82390-0
/content/journal/jgv/10.1099/vir.0.82390-0
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