Genetic Evidence that Interhelical Packing Interactions in the gp41 Core are Critical for Transition of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein to the Fusion-Active State

Citation data:

Journal of Virology, Vol: 76, Issue: 14, Page: 7356-7362

Publication Year:
2002
Usage 38
Downloads 35
Abstract Views 3
Repository URL:
https://scholarworks.umt.edu/biosci_pubs/156; https://scholarworks.umt.edu/cgi/viewcontent.cgi?article=1154&context=biosci_pubs
Author(s):
Follis, Kathryn E.; Larson, Scott J.; Lu, Min; Nunberg, Jack H.
Publisher(s):
ScholarWorks at University of Montana
Tags:
Biology; Life Sciences
article description
The envelope glycoprotein complex (gp120-gp41) of human immunodeficiency virus type 1 (HIV-1) promotes the fusion of viral and cellular membranes through formation of the fusion-active six-helix bundle in the gp41 ectodomain. This gp41 core structure consists of three C-terminal helices packed in an antiparallel manner into hydrophobic grooves on the surface of the N-terminal trimeric coiled coil. Alanine mutations that destabilize the N- and C-terminal interhelical packing interactions also reduce viral infectivity. Here we show that viruses bearing these mutations exhibit a marked potentiation of inhibition by peptides that make up the gp41 core. By contrast, these viruses are unchanged in their sensitivities to soluble CD4, the CXCR4 coreceptor ligand SDF-1alpha, and human anti-HIV immunoglobulin, reagents that impact the initial, receptor-induced conformational changes in the envelope glycoprotein. Our results support the notion that these alanine mutations specifically affect the conformational transition to the fusion-active gp41 structure. The mutations also increase viral sensitivity to the gp41-directed monoclonal antibody 2F5, suggesting that this broadly neutralizing antibody may also interfere with this transition. The conformational activation of the HIV-1 envelope glycoprotein likely represents a viable target for vaccine and antiviral drug development.