6D2P

Crystal structure of IOMA-class CLK31 Fab from an HIV-1 naive donor in complex with a germline-targeting gp120 engineered outer domain eOD-GT8 at 2.6 A

Summary for 6D2P

• Entry DOI: 10.2210/pdb6d2p/pdb
• Descriptor: Germline-targeting HIV-1 gp120 engineered outer domain eOD-GT8, IOMAclass naive CLK31 Fab heavy chain, IOMAclass naive CLK31 Fab light chain, ... (5 entities in total)
• Functional Keywords: hiv-1 gp120, engineered outer domain (eod), germline targeting, cd4 binding site, ioma-class naive human germline antibody, immune system, viral-protein complex, healthy hiv-1 negative donor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 66465.18

Authors

Sarkar, A.,Wilson, I.A. (deposition date: 2018-04-13, release date: 2019-01-16, Last modification date: 2024-10-09)

Primary citation

Havenar-Daughton, C.,Sarkar, A.,Kulp, D.W.,Toy, L.,Hu, X.,Deresa, I.,Kalyuzhniy, O.,Kaushik, K.,Upadhyay, A.A.,Menis, S.,Landais, E.,Cao, L.,Diedrich, J.K.,Kumar, S.,Schiffner, T.,Reiss, S.M.,Seumois, G.,Yates, J.R.,Paulson, J.C.,Bosinger, S.E.,Wilson, I.A.,Schief, W.R.,Crotty, S.
The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen.
Sci Transl Med, 10:-, 2018

PubMed Abstract: Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the envelope CD4-binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities () to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.

PubMed: 29973404
DOI: 10.1126/scitranslmed.aat0381

Experimental method

X-RAY DIFFRACTION (2.6 Å)