Focused evolution of HIV-1 neutralizing antibodies revealed by crystal structures and deep sequencing

US10273291B2 · kind B2 · utility

Assignees

• Duke University · US
• THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, OFFICE OF TECHNOLOGY TRANSFER—NATIONAL INSTITUTES OF HEALTH · US

Inventors

• John Mascola · Rockville, US
• Gary J. Nabel · Cambridge, US
• Barton F. Haynes · Durham, US
• Xueling Wu · Potomac, US
• Thomas B. Kepler · Boston, US
• Peter Kwong · Washington, US

Key dates

• Filing date: Mar 23, 2012
• Grant date: Apr 30, 2019
• Expiry date: Mar 23, 2032

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07K2317/76
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Antibody VRC01 represents a human immunoglobulin that neutralizes—˜90% of diverse HIV-1 isolates. To understand how such broadly neutralizing HIV-1 antibodies develop and recognize the viral envelope, we used X-ray crystallography and 454 pyrosequencing to characterize additional antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding of different antibodies to the same CD4-binding-site epitope. Antibody recognition was achieved through the evolution of complementary contact domains that were generated in diverse ways. Phylogenetic analysis of expressed heavy and light chains determined by deep sequencing revealed a common pathway of antibody heavy chain maturation confined to IGHV1-2*02 lineage that could pair with different light chains. The maturation pathway inferred by antibodyomics reveals that diverse antibodies evolve to a highly affinity-matured state to recognize an invariant viral structure, providing insight into the development and evolution of broadly neutralizing HIV-1 immunity.