期刊
AIDS RESEARCH AND HUMAN RETROVIRUSES
卷 27, 期 8, 页码 863-876出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/aid.2010.0265
关键词
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资金
- Spanish MICINN [BIO2008-00772]
- University of the Basque Country [GIU 06/42, DIPE08/12]
- Ontario Ministry of Health and Long Term Care
- Canada Research Chairs Program
- University of the Basque Country
- Canadian Institutes for Health Research
Broadly neutralizing monoclonal antibody (MAb) 2F5 targets a linear epitope within the highly conserved membrane proximal external region (MPER) of the HIV-1 envelope protein gp41 integral subunit. Prospective vaccine developments warrant efforts currently underway to unveil the mechanistic and structural basis of its mode of action. One open question relates to the putative role that membrane phospholipids might play in the neutralization process. In this work, we establish experimental conditions that allow monitoring 2F5 insertion into lipid bilayers. Then, we compare the abilities of 2F5-based MAb, Fabs, and 2F5-specific antibodies recovered from immunized rabbits to directly penetrate into lipid bilayers and block the lytic activity of MPER-derived peptides. Antibody insertion induced membrane perturbation, which was blocked on interacting with the peptide epitope, thereby suggesting that such phenomenon was primarily mediated by the epitope-binding site. The long, hydrophobic complementarity-determining region (CDR)-H3 loop contributed little to this effect. In contrast, the CDR-H3 loop was required for blocking the lytic activity of MPER-based peptides and viral neutralization. Thus, our results suggest that core epitope binding plus association with lipid bilayers are not in conjunction sufficient to support viral neutralization by 2F5. Moreover, they support a role for the CDR-H3 loop in establishing secondary interactions with lipids and/or gp41 that would block the membrane-perturbing activity of MPER during fusion.
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