Viral Escape from Neutralizing Antibodies in Early Subtype A HIV-1 Infection Drives an Increase in Autologous Neutralization Breadth

PLoS Pathogens

Saikat Boliar¹  Emmanuel Cormier²  Eric Hunter³  Paul A. Goepfert⁴  James E. Robinson⁵  Ling Yue⁶  Anurag Sethi⁶  Cynthia A. Derdeyn⁶  Ruimin Pan⁶  Megan K. Murphy⁷  Persephone Borrow⁸  Etienne Karita⁹  S. Gnanakaran⁹  Susan A. Allen^1,10  Katja Pfafferot^1,11  Xiang-Peng Kong^1,11  Jianhui Tian^1,11 

[1] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America;Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America;Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, United States of America;Departments of Epidemiology and Global Health, Emory University, Atlanta, Georgia, United States of America;Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America;Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, Georgia, United States of America;International AIDS Vaccine Initiative, Human Immunology Laboratory, Imperial College, London, United Kingdom;Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom;Projet San Francisco, Kigali, Rwanda;Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America

关键词: HIV-1;    Antibodies;    Enzyme-linked immunoassays;    Sequence alignment;    B cells;    Chemical neutralization;    293T cells;    Crystal structure;   

DOI  :  10.1371/journal.ppat.1003173

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Antibodies that neutralize (nAbs) genetically diverse HIV-1 strains have been recovered from a subset of HIV-1 infected subjects during chronic infection. Exact mechanisms that expand the otherwise narrow neutralization capacity observed during early infection are, however, currently undefined. Here we characterized the earliest nAb responses in a subtype A HIV-1 infected Rwandan seroconverter who later developed moderate cross-clade nAb breadth, using (i) envelope (Env) glycoproteins from the transmitted/founder virus and twenty longitudinal nAb escape variants, (ii) longitudinal autologous plasma, and (iii) autologous monoclonal antibodies (mAbs). Initially, nAbs targeted a single region of gp120, which flanked the V3 domain and involved the alpha2 helix. A single amino acid change at one of three positions in this region conferred early escape. One immunoglobulin heavy chain and two light chains recovered from autologous B cells comprised two mAbs, 19.3H-L1 and 19.3H-L3, which neutralized the founder Env along with one or three of the early escape variants carrying these mutations, respectively. Neither mAb neutralized later nAb escape or heterologous Envs. Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions. Resistance to mAb neutralization arose in later Envs through alteration of two glycans spatially adjacent to the initial escape signatures. The cross-neutralizing nAbs that ultimately developed failed to target any of the defined V3-proximal changes generated during the first year of infection in this subject. Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env. This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.

【 授权许可】

CC BY