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

Lülf, S.; Matz, J.; Rouyez, M. C.; Jarviluoma, A.; Saksela, K.; Benichou, S.; Geyer, M.

doi:10.1186/1742-4690-11-24

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

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Lülf, S.
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Geyer, M.
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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http://www.ncbi.nlm.nih.gov/pubmed/24620746
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Citation

Lülf, S., Matz, J., Rouyez, M. C., Jarviluoma, A., Saksela, K., Benichou, S., et al. (2014). Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody. Retrovirology, 11(1), 24. doi:10.1186/1742-4690-11-24.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-6146-C

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. RESULTS: 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. CONCLUSIONS: Together, sdAb19 and Neffin thus represent efficient tools for the rational development of antiviral strategies against HIV-1 Nef.