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Dramatic Potentiation of the Antiviral Activity of HIV Antibodies by Cholesterol Conjugation

Lacek, Krzysztof, Urbanowicz, Richard, Troise, Fulvia, De Lorenzo, Claudia, Severino, Valeria, Di Maro, Antimo, Tarr, Alexander, Ferrara, Francesca, Ploss, Alexander, Temperton, Nigel J., and others. (2014) Dramatic Potentiation of the Antiviral Activity of HIV Antibodies by Cholesterol Conjugation. Journal of Biological Chemistry, . ISSN 0021-9258. (doi:10.1074/jbc.M114.591826) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided)

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Abstract

The broadly neutralizing antibodies HIV 2F5 and 4E10, which bind to overlapping epitopes in the membrane- proximal external region (MPER) of the fusion protein gp41, have been proposed to use a two-step mechanism for neutralization: first, they bind and pre-concentrate at the viral membrane through their long, hydrophobic CDRH3 loops and second, they form a high-affinity complex with the protein epitope. Accordingly, mutagenesis of the CDRH3 can abolish their neutralizing activity, with no change in the affinity for the peptide epitope. We show here that we can mimic this mechanism by conjugating a cholesterol group outside of the paratope of an antibody. Cholesterol- conjugated antibodies bind to lipid-raft domains on the membrane and because of this enrichment, they show increased antiviral potency. In particular we find that cholesterol conjugation: (i) rescues the antiviral activity of CDRH3- mutated 2F5, (ii) increases the antiviral activity of WT 2F5, (iii) potentiates the non-membrane binding HIV antibody D5 10-100 fold (depending on the virus strain), and (iv) increases synergy between 2F5 and D5. Conjugation can be made at several positions, including variable and constant domains. Cholesterol conjugation therefore appears a general strategy to boost potency of antiviral antibodies and, since membrane affinity is engineered outside of the antibody paratope, it can complement affinity maturation strategies.

Item Type: Article
DOI/Identification number: 10.1074/jbc.M114.591826
Uncontrolled keywords: antibody engineering; cholesterol; human immunodeficiency virus (HIV); lipid raft; membrane fusion; molecular evolution; viral immunology; virus entry
Subjects: Q Science > QR Microbiology > QR355 Virology
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Nigel Temperton
Date Deposited: 21 Oct 2014 22:04 UTC
Last Modified: 29 May 2019 13:15 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/43568 (The current URI for this page, for reference purposes)
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