A Mechanistic Understanding of Allosteric Immune Escape Pathways in the HIV-1 Envelope Glycoprotein

• DOI: 10.1371/journal.pcbi.1003046
• Publication Date: 2013-05-16T21:22:32Z
• Authors: Anurag Sethi; Jianhui Tian; Cynthia A. Derdeyn; Bette Korber; S. Gnanakaran
• Keywords: Immunogen

The HIV-1 envelope (Env) spike, which consists of a compact, heterodimeric trimer the glycoproteins gp120 and gp41, is target neutralizing antibodies. However, high mutation rate plasticity Env facilitates viral evasion from antibodies through various mechanisms. Mutations that are distant antibody binding site can lead to escape, probably by changing conformation or dynamics Env; however, these changes difficult identify define mechanistically. Here we describe network analysis-based approach potential allosteric immune mechanisms using three known protein structures two different clades, B C. First, correlation principal component analyses molecular (MD) simulations identified degree long-distance coupled motions exist between functionally regions within intrinsic core, supporting presence communication in protein. Then, integrating MD with theory, optimal suboptimal pathways modules core. results unveil both strain-dependent -independent characteristics gp120. We show context structurally homologous cores, pathway for sequence sensitive, i.e. one strain becomes another strain. Yet identification conserved elements pathways, termed inter-modular hotspots, could present new opportunity immunogen design, as this be an additional mechanism uses shield vulnerable targets induce breadth.