Structural Dynamics of HIV-1 Envelope Gp120 Outer Domain with V3 Loop

Masaru Yokoyama,Hironori Sato,Satoshi Naganawa,Kazuhisa Yoshimura,Shuzo Matsushita,John J Rossi

doi:10.1371/journal.pone.0037530

Masaru Yokoyama, Hironori Sato + Show 4 more

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https://doi.org/10.1371/journal.pone.0037530

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Abstract

BackgroundThe net charge of the hypervariable V3 loop on the HIV-1 envelope gp120 outer domain plays a key role in modulating viral phenotype. However, the molecular mechanisms underlying the modulation remain poorly understood.Methodology/Principal FindingsBy combining computational and experimental approaches, we examined how V3 net charge could influence the phenotype of the gp120 interaction surface. Molecular dynamics simulations of the identical gp120 outer domain, carrying a V3 loop with net charge of +3 or +7, showed that the V3 change alone could induce global changes in fluctuation and conformation of the loops involved in binding to CD4, coreceptor and antibodies. A neutralization study using the V3 recombinant HIV-1 infectious clones showed that the virus carrying the gp120 with +3 V3, but not with +7 V3, was resistant to neutralization by anti-CD4 binding site monoclonal antibodies. An information entropy study shows that otherwise variable surface of the gp120 outer domain, such as V3 and a region around the CD4 binding loop, are less heterogeneous in the gp120 subpopulation with +3 V3.Conclusions/SignificanceThese results suggest that the HIV-1 gp120 V3 loop acts as an electrostatic modulator that influences the global structure and diversity of the interaction surface of the gp120 outer domain. Our findings will provide a novel structural basis to understand how HIV-1 adjusts relative replication fitness by V3 mutations.

Highlights

The third variable (V3) element of the human immunodeficiency virus type 1 (HIV-1) envelope gp120 protein is usually composed of 35 amino acids
Molecular dynamics simulation study To address the potential role of the V3 net charge in modulating the structure and dynamics of the gp120 surface, we performed MD simulations of the identical gp120 outer domains carrying different V3 loops with net charges of +7 or +3 (Fig. 1A)
By combining MD simulations with antibody neutralization experiments and diversity analysis of the viral protein sequences, we studied a structural basis for the phenotypic change of HIV-1 by V3 mutations

Summary

Introduction

The third variable (V3) element of the human immunodeficiency virus type 1 (HIV-1) envelope gp120 protein is usually composed of 35 amino acids. The element forms a protruding loop-like structure on the gp120 outer domain [1], is rich in basic amino acids, and has aromatic amino acids for the aromatic stacking interaction with proteins. The V3 is reported to be the major determinant of HIV-1 sensitivity to neutralization by the soluble form of CD4 [14,15,16], a recombinant protein that binds to the cleft of the gp120 core [17]. The V3 loop plays a key role in modulating biological and immunological phenotypes of HIV-1. The net charge of the hypervariable V3 loop on the HIV-1 envelope gp120 outer domain plays a key role in modulating viral phenotype.

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