Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody

Bouchet, Jérôme; Basmaciogullari, Stéphane E; Chrobak, Pavel; Stolp, Bettina; Bouchard, Nathalie; Fackler, Oliver T; Chames, Patrick; Jolicoeur, Paul; Benichou, Serge; Baty, Daniel (2011). Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody. Blood, 117(13), pp. 3559-68. Washington, D.C.: American Society of Hematology 10.1182/blood-2010-07-296749

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The Nef protein of HIV-1 is important for AIDS pathogenesis, but it is not targeted by current antiviral strategies. Here, we describe a single-domain antibody (sdAb) that binds to HIV-1 Nef with a high affinity (K(d) = 2 × 10(-9)M) and inhibited critical biologic activities of Nef both in vitro and in vivo. First, it interfered with the CD4 down-regulation activity of a broad panel of nef alleles through inhibition of the Nef effects on CD4 internalization from the cell surface. Second, it was able to interfere with the association of Nef with the cellular p21-activated kinase 2 as well as with the resulting inhibitory effect of Nef on actin remodeling. Third, it counteracted the Nef-dependent enhancement of virion infectivity and inhibited the positive effect of Nef on virus replication in peripheral blood mononuclear cells. Fourth, anti-Nef sdAb rescued Nef-mediated thymic CD4(+) T-cell maturation defects and peripheral CD4(+) T-cell activation in the CD4C/HIV-1(Nef) transgenic mouse model. Because all these Nef functions have been implicated in Nef effects on pathogenesis, this anti-Nef sdAb may represent an efficient tool to elucidate the molecular functions of Nef in the virus life cycle and could now help to develop new strategies for the control of AIDS.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Stolp, Bettina

ISSN:

0006-4971

Publisher:

American Society of Hematology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:23

Last Modified:

17 Mar 2015 21:01

Publisher DOI:

10.1182/blood-2010-07-296749

PubMed ID:

21292773

Web of Science ID:

000288999800013

URI:

https://boris.unibe.ch/id/eprint/7815 (FactScience: 213156)

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