title: Functional Mimetics of the HIV-1 CCR5 Co-Receptor Displayed on the Surface of Magnetic Liposomes.
abstract: Chemokine G protein coupled receptors, principally CCR5 or CXCR4, function as co-receptors for HIV-1 entry into CD4+ T cells. Initial binding of the viral envelope glycoprotein (Env) gp120 subunit to the host CD4 receptor induces a cascade of structural conformational changes that lead to the formation of a high-affinity co-receptor-binding site on gp120. Interaction between gp120 and the co-receptor leads to the exposure of epitopes on the viral gp41 that mediates fusion between viral and cell membranes. Soluble CD4 (sCD4) mimetics can act as an activation-based inhibitor of HIV-1 entry in vitro, as it induces similar structural changes in gp120, leading to increased virus infectivity in the short term but to virus Env inactivation in the long term. Despite promising clinical implications, sCD4 displays low efficiency in vivo, and in multiple HIV strains, it does not inhibit viral infection. This has been attributed to the slow kinetics of the sCD4-induced HIV Env inactivation and to the failure to obtain sufficient sCD4 mimetic levels in the serum. Here we present uniquely structured CCR5 co-receptor mimetics. We hypothesized that such mimetics will enhance sCD4-induced HIV Env inactivation and inhibition of HIV entry. Co-receptor mimetics were derived from CCR5 gp120-binding epitopes and functionalized with a palmitoyl group, which mediated their display on the surface of lipid-coated magnetic beads. CCR5-peptidoliposome mimetics bound to soluble gp120 and inhibited HIV-1 infectivity in a sCD4-dependent manner. We concluded that CCR5-peptidoliposomes increase the efficiency of sCD4 to inhibit HIV infection by acting as bait for sCD4-primed virus, catalyzing the premature discharge of its fusion potential.
authors.affiliation: The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Kuzmina
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Karin
authors.initials: K
authors.lastname: Vaknin
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Garik
authors.initials: G
authors.lastname: Gdalevsky
authors.affiliation: National Institute for Biotechnology in the Negev, Beer-Sheva, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Vyazmensky
authors.affiliation: National Institute for Biotechnology in the Negev, Beer-Sheva, Israel.|The Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Marks
authors.affiliation: The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Taube
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva; 2, National Institute for Biotechnology in the Negev, Beer-Sheva, Israel.|National Institute for Biotechnology in the Negev, Beer-Sheva, Israel.|The Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Engel
mesh_terms: D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008081:Liposomes; D008280:Magnetics; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D008081:Liposomes; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1