Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies
Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies
Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10(12) antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
- Duke University United States
- Columbia University United States
- Rockefeller University United States
- National Institute of Allergy and Infectious Diseases United States
B-Lymphocytes, Base Sequence, Immunology, Molecular Sequence Data, Antibodies, Monoclonal, HIV Infections, Sequence Analysis, DNA, HIV Antibodies, HIV Envelope Protein gp120, Crystallography, X-Ray, Antibodies, Neutralizing, Infectious Diseases, HIV-1, Leukocytes, Mononuclear, Immunology and Allergy, Humans, Amino Acid Sequence, Broadly Neutralizing Antibodies
B-Lymphocytes, Base Sequence, Immunology, Molecular Sequence Data, Antibodies, Monoclonal, HIV Infections, Sequence Analysis, DNA, HIV Antibodies, HIV Envelope Protein gp120, Crystallography, X-Ray, Antibodies, Neutralizing, Infectious Diseases, HIV-1, Leukocytes, Mononuclear, Immunology and Allergy, Humans, Amino Acid Sequence, Broadly Neutralizing Antibodies
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