title: In silico Analysis of HIV-1 Env-gp120 Reveals Structural Bases for Viral Adaptation in Growth-Restrictive Cells.
abstract: Variable V1/V2 and V3 loops on human immunodeficiency virus type 1 (HIV-1) envelope-gp120 core play key roles in modulating viral competence to recognize two infection receptors, CD4 and chemokine-receptors. However, molecular bases for the modulation largely remain unclear. To address these issues, we constructed structural models for a full-length gp120 in CD4-free and -bound states. The models showed topologies of gp120 surface loop that agree with those in reported structural data. Molecular dynamics simulation showed that in the unliganded state, V1/V2 loop settled into a thermodynamically stable arrangement near V3 loop for conformational masking of V3 tip, a potent neutralization epitope. In the CD4-bound state, however, V1/V2 loop was rearranged near the bound CD4 to support CD4 binding. In parallel, cell-based adaptation in the absence of anti-viral antibody pressures led to the identification of amino acid substitutions that individually enhance viral entry and growth efficiencies in association with reduced sensitivity to CCR5 antagonist TAK-779. Notably, all these substitutions were positioned on the receptors binding surfaces in V1/V2 or V3 loop. In silico structural studies predicted some physical changes of gp120 by substitutions with alterations in viral replication phenotypes. These data suggest that V1/V2 loop is critical for creating a gp120 structure that masks co-receptor binding site compatible with maintenance of viral infectivity, and for tuning a functional balance of gp120 between immune escape ability and infectivity to optimize HIV-1 replication fitness.
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Nomaguchi
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Doi
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious DiseasesTokyo, Japan; Department of Research Promotion, Division of Infectious Disease Research, Japan Agency for Medical Research and DevelopmentTokyo, Japan.
authors.forename: Tadahito
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Adachi
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Sato
keywords: MD simulation; V1/V2 loop; V3 loop; adaptive mutation; homology modeling