Network Analysis of the Communication Pathways in HIV-1 Envelope Proteins For Mechanistic Understanding of Immune Escape

Abstract

Allosteric mechanisms play a key role in the binding of the envelope protein (Env) on HIV-1 to CD4 and CCRX5 receptors on human cells, which is essential for viral entry into these cells. Env protein, gp120, has been the focus of antibody based vaccine. Phylogenetically corrected statistical methods have been used to identify amino acid signature patterns in gp120 that are differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibodies and, recently from sequences derived from serum covering a wide range of neutralizing potency. Escape mutations/signatures that are a direct consequence of antibody binding are easier to interpret. But, in many cases escape signatures are manifestations of indirect regulation of antibody access due to the conformational variability, quaternary nature and allostery of Env protein. Here we develop theoretical approaches to identify some of these indirect mechanisms by which immune escape may occur. We have performed long time simulations of three different crystal structures of gp120 representing two clades. We compare the patterns of coupled motions of different regions of gp120 using covariance, principal component and network theory analyses. We find that dominant coupled (allosteric) motions of spatially separated regions in the gp120 core are preserved across clade. However, within the same topological structural framework, the C-clade gp120 exhibits coupled motions that are slightly different from those observed for B-clade. Network analysis indicates that the communities in C-clade gp120 differ the most from B-clade gp120. Even though, gp120 from these clades are structurally similar, spatially distant sites may differentially influence conformational motions to modulate the antibody escape in a clade specific manner.