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Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody

Abstract : Background
The HIV-1 Nef protein is essential for AIDS pathogenesis by its interaction with host cell surface receptors and signaling factors. Despite its critical role as a virulence factor Nef is not targeted by current antiviral strategies.
We have determined the crystal structure of the complex formed by a camelid single-domain antibody fragment, termed sdAb19, bound to HIV-1 Nef together with a stabilizing SH3 domain. sdAb19 forms a stoichiometric 1:1 complex with Nef and binds to a conformationally conserved surface at the C-terminus of Nef that overlaps with functionally important interaction sites involved in Nef-induced perturbations of signaling and trafficking pathways. The antibody fragment binds Nef with low nanomolar affinity, which could be attenuated to micromolar affinity range by site-directed mutagenesis of key interaction residues in sdAb19. Fusion of the SH3 domain to sdAb19, termed Neffin, leads to a significantly increased affinity for Nef and formation of a stoichiometric 2:2 Nef-Neffin complex. The 19 kDa Neffin protein inhibits all functions of Nef as CD4 and MHC-I downregulation, association with Pak2, and the increase in virus infectivity and replication.
Together, sdAb19 and Neffin thus represent efficient tools for the rational development of antiviral strategies against HIV-1 Nef.
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Submitted on : Saturday, April 19, 2014 - 10:29:29 AM
Last modification on : Tuesday, May 3, 2022 - 6:26:04 PM




Sebastian Lülf, Julie Matz, Marie-Christine Rouyez, Annika Järviluoma, Kalle Saksela, et al.. Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody. Retrovirology, BioMed Central, 2014, 11 (1), pp.24. ⟨10.1186/1742-4690-11-24⟩. ⟨inserm-00980901⟩



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