title: Lipophilicity is a key factor to increase the antiviral activity of HIV neutralizing antibodies.
abstract: The HIV broadly neutralizing antibody 2F5 targets the transiently exposed epitope in the membrane proximal external region (MPER) of HIV-1 gp41, by a two-step mechanism involving the viral membrane and this viral glycoprotein. It was recently shown that 2F5 conjugation with a cholesterol moiety outside of the antibody paratope substantially increases its antiviral activity. Additionally, the antiviral activity of D5, a human antibody that binds to the N-terminal heptad repeat (NHR) of gp41 and lacks membrane binding, was boosted by the same cholesterol conjugation. In this work, we evaluated the membrane affinity of both antibodies towards membranes of different compositions, using surface plasmon resonance. A correlation was found between membrane affinity and antiviral activity against HIV-1. We propose that the conjugation of cholesterol to 2F5 or D5 allows a higher degree of antibody pre-concentration at the viral membrane. This way, the antibodies become more available to bind efficiently to the gp41 epitope, blocking viral fusion faster than the unconjugated antibody. These results set up a relevant strategy to improve the rational design of therapeutic antibodies against HIV.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Augusto
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Axel
authors.initials: A
authors.lastname: Hollmann
authors.affiliation: CEINGE Biotecnologie Avanzate S.C.R.L., Napoli, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Troise
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Veiga
authors.affiliation: PeptiPharma, Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. Electronic address: nsantos@fm.ul.pt.
authors.forename: Nuno C
authors.initials: NC
authors.lastname: Santos
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D015483:HIV Antibodies / Q000737:chemistry* / Q000494:pharmacology*; D008567:Membranes, Artificial; D009500:Neutralization Tests; D020349:Surface Plasmon Resonance
chemical_list: D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D015483:HIV Antibodies; D008567:Membranes, Artificial
keywords: Antibodies; Antiviral; HIV-1; Membrane; SPR