PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex.
Anti-HIV Agents
Capsid
/ drug effects
Capsid Proteins
/ genetics
Cell Line
DNA, Viral
/ genetics
HEK293 Cells
HIV Infections
/ drug therapy
HIV Seropositivity
/ genetics
HIV-1
/ drug effects
Humans
Indoles
/ pharmacology
Phenylalanine
/ analogs & derivatives
Reverse Transcription
/ genetics
Virus Integration
/ genetics
Virus Replication
/ drug effects
HIV-1
PF74
capsid
integration
preintegration complex
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
09
10
2018
accepted:
06
12
2018
pubmed:
21
12
2018
medline:
20
11
2019
entrez:
21
12
2018
Statut:
epublish
Résumé
The HIV-1 capsid protein (CA) facilitates reverse transcription and nuclear entry of the virus. However, CA's role in post-nuclear entry steps remains speculative. We describe a direct link between CA and integration by employing the capsid inhibitor PF74 as a probe coupled with the biochemical analysis of HIV-1 preintegration complexes (PICs) isolated from acutely infected cells. At a low micromolar concentration, PF74 potently inhibited HIV-1 infection without affecting reverse transcription. Surprisingly, PF74 markedly reduced proviral integration owing to inhibition of nuclear entry and/or integration. However, a 2-fold reduction in nuclear entry by PF74 did not quantitatively correlate with the level of antiviral activity. Titration of PF74 against the integrase inhibitor raltegravir showed an additive antiviral effect that is dependent on a block at the post-nuclear entry step. PF74's inhibitory effect was not due to the formation of defective viral DNA ends or a delay in integration, suggesting that the compound inhibits PIC-associated integration activity. Unexpectedly, PICs recovered from cells infected in the presence of PF74 exhibited elevated integration activity. PF74's effect on PIC activity is CA specific since the compound did not increase the integration activity of PICs of a PF74-resistant HIV-1 CA mutant. Sucrose gradient-based fractionation studies revealed that PICs assembled in the presence of PF74 contained lower levels of CA, suggesting a negative association between CA and PIC-associated integration activity. Finally, the addition of a CA-specific antibody or PF74 inhibited PIC-associated integration activity. Collectively, our results demonstrate that PF74's targeting of PIC-associated CA results in impaired HIV-1 integration.
Identifiants
pubmed: 30567984
pii: JVI.01741-18
doi: 10.1128/JVI.01741-18
pmc: PMC6401427
pii:
doi:
Substances chimiques
Anti-HIV Agents
0
Capsid Proteins
0
DNA, Viral
0
Indoles
0
PF-3450074
0
Phenylalanine
47E5O17Y3R
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 : P50 GM082251
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007586
Pays : United States
Organisme : NIDA NIH HHS
ID : R24 DA036420
Pays : United States
Organisme : NIDA NIH HHS
ID : R03 DA030896
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150481
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR024975
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD008149
Pays : United States
Organisme : NIDA NIH HHS
ID : R00 DA024558
Pays : United States
Organisme : NIDA NIH HHS
ID : K99 DA024558
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI076121
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136740
Pays : United States
Organisme : NIMHD NIH HHS
ID : G12 MD007586
Pays : United States
Organisme : NIDA NIH HHS
ID : R24 DA021471
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI122960
Pays : United States
Organisme : NIDA NIH HHS
ID : R03 DA033892
Pays : United States
Organisme : NCRR NIH HHS
ID : TL1 RR024978
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI076121
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007281
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI110527
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007593
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM059994
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR000447
Pays : United States
Organisme : NCRR NIH HHS
ID : U54 RR026140
Pays : United States
Organisme : NIDA NIH HHS
ID : R03 DA037779
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Microbiology.
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