title: Membrane-proximal external HIV-1 gp41 motif adapted for destabilizing the highly rigid viral envelope.
abstract: Electron microscopy structural determinations suggest that the membrane-proximal external region (MPER) of glycoprotein 41 (gp41) may associate with the HIV-1 membrane interface. It is further proposed that MPER-induced disruption and/or deformation of the lipid bilayer ensue during viral fusion. However, it is predicted that the cholesterol content of this membrane (∼45 mol %) will act against MPER binding and restructuring activity, in agreement with alternative structural models proposing that the MPER constitutes a gp41 ectodomain component that does not insert into the viral membrane. Here, using MPER-based peptides, we test the hypothesis that cholesterol impedes the membrane association and destabilizing activities of this gp41 domain. To that end, partitioning and leakage assays carried out in lipid vesicles were combined with x-ray reflectivity and grazing-incidence diffraction studies of monolayers. CpreTM, a peptide combining the carboxyterminal MPER sequence with aminoterminal residues of the transmembrane domain, bound and destabilized effectively cholesterol-enriched membranes. Accordingly, virion incubation with this peptide inhibited cell infection potently but nonspecifically. Thus, CpreTM seems to mimic the envelope-perturbing function of the MPER domain and displays antiviral activity. As such, we infer that CpreTM bound to cholesterol-enriched membranes would represent a relevant target for anti-HIV-1 immunogen and inhibitor development.
authors.affiliation: Biophysics Unit (CSIC-UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country, Bilbao, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Apellániz
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivankin
authors.forename: Shlomo
authors.initials: S
authors.lastname: Nir
authors.forename: David
authors.initials: D
authors.lastname: Gidalevitz
authors.forename: José L
authors.initials: JL
authors.lastname: Nieva
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002213:Capsid / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism* / Q000472:pathogenicity; D008567:Membranes, Artificial; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D015700:HIV Envelope Protein gp41; D008567:Membranes, Artificial; D010455:Peptides; D010713:Phosphatidylcholines; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
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