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ID 116583
Title Alternative
V3 Tip-Dependent Species Specificity of HIV-1 Env
Author
Yokoyama, Masaru National Institute of Infectious Diseases
Kotani, Osamu National Institute of Infectious Diseases
Nakanishi, Nina Tokushima University
Okubo, Hayato Tokushima University
Adachi, Shun Kansai Medical University
Sato, Hironori National Institute of Infectious Diseases
Keywords
HIV-1
Env-gp120
CD4
CCR5
V3 loop
adaptive mutation
species specificity
in silico structural analysis
Content Type
Journal Article
Description
Molecular interactions of the variable envelope gp120 subunit of HIV-1 with two cellular receptors are the first step of viral infection, thereby playing pivotal roles in determining viral infectivity and cell tropism. However, the underlying regulatory mechanisms for interactions under gp120 spontaneous variations largely remain unknown. Here, we show an allosteric mechanism in which a single gp120 mutation remotely controls the ternary interactions between gp120 and its receptors for the switch of viral cell tropism. Virological analyses showed that a G310R substitution at the tip of the gp120 V3 loop selectively abolished the viral replication ability in human cells, despite evoking enhancement of viral replication in macaque cells. Molecular dynamics (MD) simulations predicted that the G310R substitution at a site away from the CD4 interaction site selectively impeded the binding ability of gp120 to human CD4. Consistently, virions with the G310R substitution exhibited a reduced binding ability to human lymphocyte cells. Furthermore, the G310R substitution influenced the gp120-CCR5 interaction in a CCR5-type dependent manner as assessed by MD simulations and an infectivity assay using exogenously expressed CCR5s. Interestingly, an I198M mutation in human CCR5 restored the infectivity of the G310R virus in human cells. Finally, MD simulation predicted amino acid interplays that physically connect the V3 loop and gp120 elements for the CD4 and CCR5 interactions. Collectively, these results suggest that the V3 loop tip is a cis-allosteric regulator that remotely controls intra- and intermolecular interactions of HIV-1 gp120 for balancing ternary interactions with CD4 and CCR5.
Journal Title
Journal of Virology
ISSN
10985514
NCID
AA12024806
Publisher
American Society for Microbiology
Volume
95
Issue
13
Start Page
e02177-20
Published Date
2021-06-10
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
Medical Sciences