Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations.
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.
Program in Molecular Medicine, Biotech 2, University of Massachusetts Medical School, Worcester, United States of America.
Maria
M
Duenas-Decamp
Biochemistry and Molecular Pharmacology, Lazare Research Building, University of Massachusetts Medical School, Worcester, United States of America.
Li
L
Jiang
Biochemistry and Molecular Pharmacology, Lazare Research Building, University of Massachusetts Medical School, Worcester, United States of America.
Daniel
D
Bolon
Program in Molecular Medicine, Biotech 2, University of Massachusetts Medical School, Worcester, United States of America.
Paul R
PR
Clapham
D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000821:virology; D016296:Mutagenesis; D011487:Protein Conformation; D012367:RNA, Viral / Q000737:chemistry
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D012367:RNA, Viral