In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection

Liza M. Cabuang, Tim Shaw, Margaret Littlejohn, Danni Colledge, Vitini Sozzi, Sally Soppe, Nadia Warner, Alex Thompson, Scott Preiss, Natasha Lam, Renae Walsh, Sharon R. Lewin, Chloe L Thio, Gail Matthews, Stephen A. Locarnini, Peter A. Revill

Research output: Contribution to journalArticle

Abstract

The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at 64Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B "e" antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the -1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the -1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the -1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of -1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the -1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection.

Original languageEnglish (US)
Pages (from-to)1166-1176
Number of pages11
JournalJournal of Medical Virology
Volume84
Issue number8
DOIs
StatePublished - Aug 2012

Fingerprint

Coinfection
Hepatitis B virus
HIV Infections
Hepatitis B e Antigens
Phenotype
HIV
Genes
Viruses
Nucleocapsid
Proteins
Protein Precursors
Nonsense Codon
Guanine
Golgi Apparatus
DNA Replication
Codon
Endoplasmic Reticulum
Hepatocellular Carcinoma
Complementary DNA
Cell Culture Techniques

Keywords

  • Co-infection, precore, HBeAg, virus replication, ER stress
  • HBV
  • HIV

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Cabuang, L. M., Shaw, T., Littlejohn, M., Colledge, D., Sozzi, V., Soppe, S., ... Revill, P. A. (2012). In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection. Journal of Medical Virology, 84(8), 1166-1176. https://doi.org/10.1002/jmv.23328

In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection. / Cabuang, Liza M.; Shaw, Tim; Littlejohn, Margaret; Colledge, Danni; Sozzi, Vitini; Soppe, Sally; Warner, Nadia; Thompson, Alex; Preiss, Scott; Lam, Natasha; Walsh, Renae; Lewin, Sharon R.; Thio, Chloe L; Matthews, Gail; Locarnini, Stephen A.; Revill, Peter A.

In: Journal of Medical Virology, Vol. 84, No. 8, 08.2012, p. 1166-1176.

Research output: Contribution to journalArticle

Cabuang, LM, Shaw, T, Littlejohn, M, Colledge, D, Sozzi, V, Soppe, S, Warner, N, Thompson, A, Preiss, S, Lam, N, Walsh, R, Lewin, SR, Thio, CL, Matthews, G, Locarnini, SA & Revill, PA 2012, 'In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection', Journal of Medical Virology, vol. 84, no. 8, pp. 1166-1176. https://doi.org/10.1002/jmv.23328
Cabuang, Liza M. ; Shaw, Tim ; Littlejohn, Margaret ; Colledge, Danni ; Sozzi, Vitini ; Soppe, Sally ; Warner, Nadia ; Thompson, Alex ; Preiss, Scott ; Lam, Natasha ; Walsh, Renae ; Lewin, Sharon R. ; Thio, Chloe L ; Matthews, Gail ; Locarnini, Stephen A. ; Revill, Peter A. / In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection. In: Journal of Medical Virology. 2012 ; Vol. 84, No. 8. pp. 1166-1176.
@article{7b32f3748bb044a19eaf752e9392be3f,
title = "In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection",
abstract = "The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at 64Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B {"}e{"} antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the -1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the -1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the -1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of -1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the -1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection.",
keywords = "Co-infection, precore, HBeAg, virus replication, ER stress, HBV, HIV",
author = "Cabuang, {Liza M.} and Tim Shaw and Margaret Littlejohn and Danni Colledge and Vitini Sozzi and Sally Soppe and Nadia Warner and Alex Thompson and Scott Preiss and Natasha Lam and Renae Walsh and Lewin, {Sharon R.} and Thio, {Chloe L} and Gail Matthews and Locarnini, {Stephen A.} and Revill, {Peter A.}",
year = "2012",
month = "8",
doi = "10.1002/jmv.23328",
language = "English (US)",
volume = "84",
pages = "1166--1176",
journal = "Journal of Medical Virology",
issn = "0146-6615",
publisher = "Wiley-Liss Inc.",
number = "8",

}

TY - JOUR

T1 - In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection

AU - Cabuang, Liza M.

AU - Shaw, Tim

AU - Littlejohn, Margaret

AU - Colledge, Danni

AU - Sozzi, Vitini

AU - Soppe, Sally

AU - Warner, Nadia

AU - Thompson, Alex

AU - Preiss, Scott

AU - Lam, Natasha

AU - Walsh, Renae

AU - Lewin, Sharon R.

AU - Thio, Chloe L

AU - Matthews, Gail

AU - Locarnini, Stephen A.

AU - Revill, Peter A.

PY - 2012/8

Y1 - 2012/8

N2 - The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at 64Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B "e" antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the -1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the -1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the -1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of -1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the -1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection.

AB - The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at 64Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B "e" antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the -1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the -1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the -1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of -1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the -1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection.

KW - Co-infection, precore, HBeAg, virus replication, ER stress

KW - HBV

KW - HIV

UR - http://www.scopus.com/inward/record.url?scp=84862654949&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862654949&partnerID=8YFLogxK

U2 - 10.1002/jmv.23328

DO - 10.1002/jmv.23328

M3 - Article

C2 - 22711344

AN - SCOPUS:84862654949

VL - 84

SP - 1166

EP - 1176

JO - Journal of Medical Virology

JF - Journal of Medical Virology

SN - 0146-6615

IS - 8

ER -