Single Hepatocyte Hepatitis B Virus Transcriptional Landscape in HIV Coinfection.
HBV transcription
HIV/HBV coinfection
intrahepatic hepatitis B
single-cell laser capture microdissection
viral landscape
viroscape
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
07 04 2020
07 04 2020
Historique:
received:
14
08
2019
accepted:
18
11
2019
pubmed:
20
11
2019
medline:
5
2
2021
entrez:
20
11
2019
Statut:
ppublish
Résumé
Hepatitis B virus (HBV) is a leading cause of liver failure and hepatocellular carcinoma. Approximately 10% of people with HIV also have HBV and are at higher risk of liver disease progression than in HBV monoinfection. Antivirals, common to HIV and HBV, suppress HBV DNA levels but do not eradicate virus because the transcriptional template, covalently closed circular DNA (cccDNA), is long lived in infected hepatocytes. Using single-cell laser capture microdissection, we isolated >1100 hepatocytes from 5 HIV/HBV coinfected persons with increasing exposure to HBV antivirals (HB1-HB5; no exposure to >7 years exposure), quantifying cccDNA and pregenomic RNA (pgRNA) in each cell using droplet digital polymerase chain reaction. The proportion of infected hepatocytes decreased with antiviral exposure from 96.4% (HB1) to 29.8% (HB5). Upper cccDNA range and median pgRNA decreased from HB1 to HB5 (P < .05 for both). The amount of pgRNA transcribed per cccDNA also decreased from HB1 to HB5 (P < .05). Cells with inactive pgRNA transcription were enriched from 0% (HB1) to 14.3% (HB5) of infected hepatocytes. cccDNA transcription is reduced in HIV/HBV coinfected people with longer antiviral duration. Understanding HBV transcriptional regulation may be critical to develop a functional cure.
Sections du résumé
BACKGROUND
Hepatitis B virus (HBV) is a leading cause of liver failure and hepatocellular carcinoma. Approximately 10% of people with HIV also have HBV and are at higher risk of liver disease progression than in HBV monoinfection. Antivirals, common to HIV and HBV, suppress HBV DNA levels but do not eradicate virus because the transcriptional template, covalently closed circular DNA (cccDNA), is long lived in infected hepatocytes.
METHODS
Using single-cell laser capture microdissection, we isolated >1100 hepatocytes from 5 HIV/HBV coinfected persons with increasing exposure to HBV antivirals (HB1-HB5; no exposure to >7 years exposure), quantifying cccDNA and pregenomic RNA (pgRNA) in each cell using droplet digital polymerase chain reaction.
RESULTS
The proportion of infected hepatocytes decreased with antiviral exposure from 96.4% (HB1) to 29.8% (HB5). Upper cccDNA range and median pgRNA decreased from HB1 to HB5 (P < .05 for both). The amount of pgRNA transcribed per cccDNA also decreased from HB1 to HB5 (P < .05). Cells with inactive pgRNA transcription were enriched from 0% (HB1) to 14.3% (HB5) of infected hepatocytes.
CONCLUSIONS
cccDNA transcription is reduced in HIV/HBV coinfected people with longer antiviral duration. Understanding HBV transcriptional regulation may be critical to develop a functional cure.
Identifiants
pubmed: 31740931
pii: 5628941
doi: 10.1093/infdis/jiz607
pmc: PMC7137881
doi:
Substances chimiques
DNA, Circular
0
DNA, Viral
0
Hepatitis B e Antigens
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
Pagination
1462-1469Subventions
Organisme : NIAID NIH HHS
ID : R01 AI116269
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI116868
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI138810
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK094818
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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