Strain-Dependent Activation and Inhibition of Human Immunodeficiency Virus Entry by a Specific PF-68742 Stereoisomer.
Antiviral Agents
/ pharmacology
CD4-Positive T-Lymphocytes
/ drug effects
HIV Envelope Protein gp120
/ chemistry
HIV Envelope Protein gp41
/ chemistry
HIV Infections
/ drug therapy
HIV-1
/ classification
Humans
Protein Binding
Protein Conformation
Protein Multimerization
Pyridones
/ chemistry
Receptors, CCR5
/ genetics
Stereoisomerism
Sulfonamides
/ chemistry
Virus Internalization
/ drug effects
Virus Replication
CD4 independent
Env
antibody
conformational change
inhibitor
mutant
retrovirus
sensitization
variation
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
01 11 2019
01 11 2019
Historique:
received:
18
07
2019
accepted:
03
08
2019
pubmed:
9
8
2019
medline:
11
6
2020
entrez:
9
8
2019
Statut:
epublish
Résumé
Human immunodeficiency virus (HIV-1) entry into cells is mediated by the viral envelope glycoprotein (Env) trimer, which consists of three gp120 exterior glycoproteins and three gp41 transmembrane glycoproteins. When gp120 binds sequentially to the receptors CD4 and CCR5 on the target cell, the metastable Env trimer is triggered to undergo entry-related conformational changes. PF-68742 is a small molecule that inhibits the infection of a subset of HIV-1 strains by interfering with an Env function other than receptor binding. Determinants of HIV-1 resistance to PF-68742 map to the disulfide loop and fusion peptide of gp41. Of the four possible PF-68742 stereoisomers, only one, MF275, inhibited the infection of CD4-positive CCR5-positive cells by some HIV-1 strains. MF275 inhibition of these HIV-1 strains occurred after CD4 binding but before the formation of the gp41 six-helix bundle. Unexpectedly, MF275 activated the infection of CD4-negative CCR5-positive cells by several HIV-1 strains resistant to the inhibitory effects of the compound in CD4-positive target cells. In contrast to CD4 complementation by CD4-mimetic compounds, activation of CD4-independent infection by MF275 did not depend upon the availability of the gp120 Phe 43 cavity. Sensitivity to inhibitors indicates that MF275-activated virus entry requires formation/exposure of the gp41 heptad repeat (HR1) as well as CCR5 binding. MF275 apparently activates a virus entry pathway parallel to that triggered by CD4 and CD4-mimetic compounds. Strain-dependent divergence in Env conformational transitions allows different outcomes, inhibition or activation, in response to MF275. Understanding the mechanisms of MF275 activity should assist efforts to optimize its utility.
Identifiants
pubmed: 31391272
pii: JVI.01197-19
doi: 10.1128/JVI.01197-19
pmc: PMC6803283
pii:
doi:
Substances chimiques
Antiviral Agents
0
HIV Envelope Protein gp120
0
HIV Envelope Protein gp41
0
PF 68742
0
Pyridones
0
Receptors, CCR5
0
Sulfonamides
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 : NIAID NIH HHS
ID : P01 AI150471
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124982
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Microbiology.
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