Effects of the SOS (A501C/T605C) and DS (I201C/A433C) Disulfide Bonds on HIV-1 Membrane Envelope Glycoprotein Conformation and Function.
Antibodies, Neutralizing
/ immunology
Disulfides
/ immunology
Genes, env
/ genetics
HEK293 Cells
HIV Antibodies
/ immunology
HIV Envelope Protein gp120
/ immunology
HIV Envelope Protein gp41
/ immunology
HIV-1
/ immunology
Humans
Membrane Glycoproteins
/ immunology
Protein Conformation
Structure-Activity Relationship
Viral Envelope Proteins
/ genetics
Virus Internalization
env Gene Products, Human Immunodeficiency Virus
/ genetics
Env
HIV-1
antibody
inhibitor
mutant
retrovirus
structure
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
15 06 2019
15 06 2019
Historique:
received:
20
02
2019
accepted:
29
03
2019
pubmed:
5
4
2019
medline:
24
6
2020
entrez:
5
4
2019
Statut:
epublish
Résumé
Most broadly neutralizing antibodies and many entry inhibitors target the pretriggered (state 1) conformation of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env). Here we examine two previously reported Env mutants designed to be stabilized in this conformation by the introduction of artificial disulfide bonds: A501C/T605C (called SOS) and I201C/A433C (called DS). SOS Env supported virus entry and cell-cell fusion only after exposure to a reducing agent, dithiothreitol (DTT). Deletion of the Env cytoplasmic tail improved the efficiency with which the SOS Env supported virus infection in a reducing environment. The antigenicity of the SOS Env was similar to that of the unmodified Env, except for greater sensitivity to some state 1-preferring ligands. In contrast, viruses with the DS Env were not infectious, even after DTT treatment. The proteolytic maturation of the DS Env on both cell surfaces and virions was severely compromised compared with that of the unmodified Env. The DS Env exhibited detectable cell-fusing activity when DTT was present. However, the profiles of cell-surface Env recognition and cell-cell fusion inhibition by antibodies differed for the DS Env and the unmodified Env. Thus, the DS Env appears to be stabilized in an off-pathway conformation that is nonfunctional on the virus. The SOS change exerted more subtle, context-dependent effects on Env conformation and function.
Identifiants
pubmed: 30944182
pii: JVI.00304-19
doi: 10.1128/JVI.00304-19
pmc: PMC6613753
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Disulfides
0
HIV Antibodies
0
HIV Envelope Protein gp120
0
HIV Envelope Protein gp41
0
Membrane Glycoproteins
0
Viral Envelope Proteins
0
env Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : P01 GM056550
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124982
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI145547
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI100645
Pays : United States
Organisme : CIHR
Pays : Canada
Informations de copyright
Copyright © 2019 American Society for Microbiology.
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