Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations

PLoS Pathogens

Daniel Bolon¹  Li Jiang¹  Paul R. Clapham²  Maria Duenas-Decamp² 

[1] Biochemistry and Molecular Pharmacology, Lazare Research Building, University of Massachusetts Medical School, Worcester, United States of America;Program in Molecular Medicine, Biotech 2, University of Massachusetts Medical School, Worcester, United States of America

关键词: Substitution mutation;    Macrophages;    Viral replication;    HIV-1;    293T cells;    Antibodies;    Mutation databases;    HIV;   

DOI  :  10.1371/journal.ppat.1005988

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The conformation of HIV-1 envelope (Env) glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs) for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD) was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines.

【 授权许可】

CC BY