4Z0X

Structure of Hepatitis C Virus Envelope glycoprotein E2 antigenic region 434-446 bound to the broadly neutralizing antibody HC26AM

Summary for 4Z0X

• Entry DOI: 10.2210/pdb4z0x/pdb
• Descriptor: Antibody HC26AM light chain variable domain, Antibody HC26AM heavy chain variable domain, HCV E2 Antigen (residues 432-446), ... (4 entities in total)
• Functional Keywords: hcv, broadly neutralizing antibody, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 25641.42

Authors

Rangarajan, S.,Shahid, S.,Mariuzza, R.A. (deposition date: 2015-03-26, release date: 2016-07-20, Last modification date: 2024-10-23)

Primary citation

Keck, Z.Y.,Wang, Y.,Lau, P.,Lund, G.,Rangarajan, S.,Fauvelle, C.,Liao, G.C.,Holtsberg, F.W.,Warfield, K.L.,Aman, M.J.,Pierce, B.G.,Fuerst, T.R.,Bailey, J.R.,Baumert, T.F.,Mariuzza, R.A.,Kneteman, N.M.,Foung, S.K.
Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice.
Hepatology, 64:1922-1933, 2016

PubMed Abstract: Direct-acting antivirals (DAAs) have led to a high cure rate in treated patients with chronic hepatitis C virus (HCV) infection, but this still leaves a large number of treatment failures secondary to the emergence of resistance-associated variants (RAVs). To increase the barrier to resistance, a complementary strategy is to use neutralizing human monoclonal antibodies (HMAbs) to prevent acute infection. However, earlier efforts with the selected antibodies led to RAVs in animal and clinical studies. Therefore, we identified an HMAb that is less likely to elicit RAVs for affinity maturation to increase potency and, more important, breadth of protection. Selected matured antibodies show improved affinity and neutralization against a panel of diverse HCV isolates. Structural and modeling studies reveal that the affinity-matured HMAb mediates virus neutralization, in part, by inducing conformational change to the targeted epitope, and that the maturated light chain is responsible for the improved affinity and breadth of protection. A matured HMAb protected humanized mice when challenged with an infectious HCV human serum inoculum for a prolonged period. However, a single mouse experienced breakthrough infection after 63 days when the serum HMAb concentration dropped by several logs; sequence analysis revealed no viral escape mutation.

PubMed: 27641232
DOI: 10.1002/hep.28850

Experimental method

X-RAY DIFFRACTION (2 Å)