Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization
Copyright policy )Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization
AbstractThe V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of V3-base bnAbs. While most bnAbs target prefusion Env, V3-crown bnDs bind open Env conformations triggered by CD4 engagement. BnDs achieve breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3. We further show that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth. Our results indicate a role of V3-crown responses and its conformational preferences in bnAb development to be considered in preventive and therapeutic approaches.
- University of Zurich Switzerland
- Language, Reasoning and Education Lab Department of Computer Science ETH Zürich Switzerland
- Universita della Svizzera Italiana Switzerland
- Vaccine Research Center
- University Hospital of Zurich Switzerland
10028 Institute of Medical Virology, Protein Conformation, /145, Science, /49/47, 610 Medicine & health, 1600 General Chemistry, HIV Antibodies, Molecular Dynamics Simulation, Article, /38/70, 10234 Clinic for Infectious Diseases, Epitopes, /13/1, 1300 General Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, /692/699/255/1901, 10019 Department of Biochemistry, /631/45/612/1256, Humans, Q, env Gene Products, Human Immunodeficiency Virus, article, Antibodies, Neutralizing, 3100 General Physics and Astronomy, Molecular Docking Simulation, /13/31, HEK293 Cells, Immunoglobulin G, Mutation, HIV-1, 570 Life sciences; biology, /631/326/596/1296, /631/45/535/1266, /631/250/2152/2153/1291, Protein Binding
10028 Institute of Medical Virology, Protein Conformation, /145, Science, /49/47, 610 Medicine & health, 1600 General Chemistry, HIV Antibodies, Molecular Dynamics Simulation, Article, /38/70, 10234 Clinic for Infectious Diseases, Epitopes, /13/1, 1300 General Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, /692/699/255/1901, 10019 Department of Biochemistry, /631/45/612/1256, Humans, Q, env Gene Products, Human Immunodeficiency Virus, article, Antibodies, Neutralizing, 3100 General Physics and Astronomy, Molecular Docking Simulation, /13/31, HEK293 Cells, Immunoglobulin G, Mutation, HIV-1, 570 Life sciences; biology, /631/326/596/1296, /631/45/535/1266, /631/250/2152/2153/1291, Protein Binding
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).15 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!