Conformational Engineering of HIV-1 Env Based on Mutational Tolerance in the CD4 and PG16 Bound States
Copyright policy )Conformational Engineering of HIV-1 Env Based on Mutational Tolerance in the CD4 and PG16 Bound States
HIV-1 Env is dynamic and undergoes large conformational changes that drive fusion of virus and host cell membranes. Three Env proteins in a trimer contact each other at their apical tips to form a closed conformation that presents epitopes recognized by broadly neutralizing antibodies. The apical tips separate, among other changes, to form an open conformation that binds tightly to host receptors. Understanding how Env sequence facilitates these structural changes can inform the biophysical mechanism and aid immunogen design. Using deep mutational scans decoupled from virus replication, we report mutational landscapes for Env from two strains interacting with conformation-dependent binding proteins. Residues in the Env trimer interface and apical domains are preferentially conserved in the closed conformation, and conformational diversity is facilitated by electrostatic repulsion and an underpacked core between domains. Specific mutations are described that enhance presentation of the trimeric closed conformation across diverse HIV-1 strains.
- University of Illinois at Urbana Champaign United States
- University of Illinois at Urbana–Champaign United States
CD4-Positive T-Lymphocytes, Models, Molecular, Protein Conformation, env Gene Products, Human Immunodeficiency Virus, HIV Infections, HIV Antibodies, HIV Envelope Protein gp120, Virus Internalization, Protein Engineering, Antibodies, Neutralizing, Cell Line, Epitopes, CD4 Antigens, HIV Seropositivity, Mutation, HIV-1, Humans, Protein Multimerization, Protein Structure, Quaternary, Protein Binding
CD4-Positive T-Lymphocytes, Models, Molecular, Protein Conformation, env Gene Products, Human Immunodeficiency Virus, HIV Infections, HIV Antibodies, HIV Envelope Protein gp120, Virus Internalization, Protein Engineering, Antibodies, Neutralizing, Cell Line, Epitopes, CD4 Antigens, HIV Seropositivity, Mutation, HIV-1, Humans, Protein Multimerization, Protein Structure, Quaternary, Protein Binding
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