8UKI

Crystal structure of 04_A06 Fab

Summary for 8UKI

• Entry DOI: 10.2210/pdb8uki/pdb
• Descriptor: 04_A06 Fab Heavy Chain, 04_A06 Fab Light Chain (3 entities in total)
• Functional Keywords: fab, broadly neutralizing antibody, hiv-1, cd4 binding site, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 49833.52

Authors

DeLaitsch, A.T.,Gristick, H.B.,Bjorkman, P.J. (deposition date: 2023-10-13, release date: 2025-04-16, Last modification date: 2025-10-29)

Primary citation

Gieselmann, L.,DeLaitsch, A.T.,Rohde, M.,Gruell, H.,Kreer, C.,Ercanoglu, M.S.,Gristick, H.B.,Schommers, P.,Ahmadov, E.,Radford, C.,Mazzolini, A.,Zhang, L.,West Jr., A.P.,Worczinski, J.,Momot, A.,Reichwein, M.L.,Knufer, J.,Stumpf, R.,Mkhize, N.N.,Kaldine, H.,Bhebhe, S.,Deshpande, S.,Giovannoni, F.,Stefanutti, E.,Benigni, F.,Havenar-Daughton, C.,Corti, D.,Kroidl, A.,Adhikari, A.,Nanfack, A.J.,Ambada, G.E.,Duerr, R.,Maganga, L.,William, W.,Ntinginya, N.E.,Wolf, T.,Geldmacher, C.,Hoelscher, M.,Lehmann, C.,Moore, P.L.,Mora, T.,Walczak, A.M.,Gilbert, P.B.,Doria-Rose, N.A.,Huang, Y.,Bloom, J.D.,Seaman, M.S.,Bjorkman, P.J.,Klein, F.
Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy.
Nat.Immunol., 2025

PubMed Abstract: Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a V1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.

PubMed: 41053396
DOI: 10.1038/s41590-025-02286-5

Experimental method

X-RAY DIFFRACTION (1.75 Å)