Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of Infectious Virus

[Guest guest]

http://jvi.asm.org/cgi/content/abstract/84/22/11994

Journal of Virology, November 2010, p. 11994-12001, Vol. 84, No. 22

0022-538X/10/$012.00+0 doi:10.1128/JVI.00653-10

, American Society for Microbiology. .

Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of

Infectious Virus

Silke Arzberger,1,2 nna Hösel,2 and Ulrike Protzer1*

Institute of Virology, Technische Universität München/Helmholtz Zentrum München,

Trogerstr. 30, D-81675 Munich, Germany,1 Center for Molecular Medicine Cologne

(ZMMK), Institute for Medical Microbiology, Immunology, and Hygiene, University

of Cologne, f Stelzmann Str. 19-21, D-50935 Koeln, Germany2

Received 26 March 2010/ Accepted 10 August 2010

Apoptosis of infected cells is critically involved in antiviral defense.

Apoptosis, however, may also support the release and spread of viruses. Although

the elimination of infected hepatocytes is required to combat hepatitis B virus

(HBV) infection, it is still unknown which consequences hepatocyte apoptosis has

for the virus and whether or not it is advantageous to the virus. To study this,

we designed a cell culture model consisting of both HBV-producing cell lines and

primary human hepatocytes serving as an infection model. We showed that the

release of mature, enveloped virions was 80% to 90% reduced 24 h after the

induction of apoptosis in HBV-replicating hepatoma cells or HBV-infected

hepatocytes. Importantly, HBV particles released from apoptotic hepatocytes were

immature and nonenveloped and proved not to be infectious. We found an inverse

correlation between the strength of an apoptotic stimulus and the infectivity of

the virus particles released: the more potent the apoptotic stimulus, the higher

the ratio of nonenveloped capsids to virions and the lower their infectivity.

Furthermore, we demonstrated that HBV replication and, particularly, the

expression of the HBx protein transcribed from the viral genome during

replication do not sensitize cells to apoptosis. Our data clearly reject the

hypothesis that the apoptosis of infected hepatocytes facilitates the

propagation of HBV. Rather, these data indicate that HBV needs to prevent the

apoptosis of its host hepatocyte to ensure the release of infectious progeny

and, thus, virus spread in the liver.

--------------------------------------------------------------------------------

* Corresponding author. Mailing address: Institute of Virology Technische,

Universität München/Helmholtz Zentrum München, Trogerstr. 30, D-81675 München,

Germany. Phone: 49-89-41406821. Fax: 49-89-41406823. E-mail: protzer@...

[Guest guest]

http://jvi.asm.org/cgi/content/abstract/84/22/11994

Journal of Virology, November 2010, p. 11994-12001, Vol. 84, No. 22

0022-538X/10/$012.00+0 doi:10.1128/JVI.00653-10

, American Society for Microbiology. .

Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of

Infectious Virus

Silke Arzberger,1,2 nna Hösel,2 and Ulrike Protzer1*

Institute of Virology, Technische Universität München/Helmholtz Zentrum München,

Trogerstr. 30, D-81675 Munich, Germany,1 Center for Molecular Medicine Cologne

(ZMMK), Institute for Medical Microbiology, Immunology, and Hygiene, University

of Cologne, f Stelzmann Str. 19-21, D-50935 Koeln, Germany2

Received 26 March 2010/ Accepted 10 August 2010

Apoptosis of infected cells is critically involved in antiviral defense.

Apoptosis, however, may also support the release and spread of viruses. Although

the elimination of infected hepatocytes is required to combat hepatitis B virus

(HBV) infection, it is still unknown which consequences hepatocyte apoptosis has

for the virus and whether or not it is advantageous to the virus. To study this,

we designed a cell culture model consisting of both HBV-producing cell lines and

primary human hepatocytes serving as an infection model. We showed that the

release of mature, enveloped virions was 80% to 90% reduced 24 h after the

induction of apoptosis in HBV-replicating hepatoma cells or HBV-infected

hepatocytes. Importantly, HBV particles released from apoptotic hepatocytes were

immature and nonenveloped and proved not to be infectious. We found an inverse

correlation between the strength of an apoptotic stimulus and the infectivity of

the virus particles released: the more potent the apoptotic stimulus, the higher

the ratio of nonenveloped capsids to virions and the lower their infectivity.

Furthermore, we demonstrated that HBV replication and, particularly, the

expression of the HBx protein transcribed from the viral genome during

replication do not sensitize cells to apoptosis. Our data clearly reject the

hypothesis that the apoptosis of infected hepatocytes facilitates the

propagation of HBV. Rather, these data indicate that HBV needs to prevent the

apoptosis of its host hepatocyte to ensure the release of infectious progeny

and, thus, virus spread in the liver.

--------------------------------------------------------------------------------

* Corresponding author. Mailing address: Institute of Virology Technische,

Universität München/Helmholtz Zentrum München, Trogerstr. 30, D-81675 München,

Germany. Phone: 49-89-41406821. Fax: 49-89-41406823. E-mail: protzer@...

[Guest guest]

http://jvi.asm.org/cgi/content/abstract/84/22/11994

Journal of Virology, November 2010, p. 11994-12001, Vol. 84, No. 22

0022-538X/10/$012.00+0 doi:10.1128/JVI.00653-10

, American Society for Microbiology. .

Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of

Infectious Virus

Silke Arzberger,1,2 nna Hösel,2 and Ulrike Protzer1*

Institute of Virology, Technische Universität München/Helmholtz Zentrum München,

Trogerstr. 30, D-81675 Munich, Germany,1 Center for Molecular Medicine Cologne

(ZMMK), Institute for Medical Microbiology, Immunology, and Hygiene, University

of Cologne, f Stelzmann Str. 19-21, D-50935 Koeln, Germany2

Received 26 March 2010/ Accepted 10 August 2010

Apoptosis of infected cells is critically involved in antiviral defense.

Apoptosis, however, may also support the release and spread of viruses. Although

the elimination of infected hepatocytes is required to combat hepatitis B virus

(HBV) infection, it is still unknown which consequences hepatocyte apoptosis has

for the virus and whether or not it is advantageous to the virus. To study this,

we designed a cell culture model consisting of both HBV-producing cell lines and

primary human hepatocytes serving as an infection model. We showed that the

release of mature, enveloped virions was 80% to 90% reduced 24 h after the

induction of apoptosis in HBV-replicating hepatoma cells or HBV-infected

hepatocytes. Importantly, HBV particles released from apoptotic hepatocytes were

immature and nonenveloped and proved not to be infectious. We found an inverse

correlation between the strength of an apoptotic stimulus and the infectivity of

the virus particles released: the more potent the apoptotic stimulus, the higher

the ratio of nonenveloped capsids to virions and the lower their infectivity.

Furthermore, we demonstrated that HBV replication and, particularly, the

expression of the HBx protein transcribed from the viral genome during

replication do not sensitize cells to apoptosis. Our data clearly reject the

hypothesis that the apoptosis of infected hepatocytes facilitates the

propagation of HBV. Rather, these data indicate that HBV needs to prevent the

apoptosis of its host hepatocyte to ensure the release of infectious progeny

and, thus, virus spread in the liver.

--------------------------------------------------------------------------------

* Corresponding author. Mailing address: Institute of Virology Technische,

Universität München/Helmholtz Zentrum München, Trogerstr. 30, D-81675 München,

Germany. Phone: 49-89-41406821. Fax: 49-89-41406823. E-mail: protzer@...

[Guest guest]

http://jvi.asm.org/cgi/content/abstract/84/22/11994

Journal of Virology, November 2010, p. 11994-12001, Vol. 84, No. 22

0022-538X/10/$012.00+0 doi:10.1128/JVI.00653-10

, American Society for Microbiology. .

Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of

Infectious Virus

Silke Arzberger,1,2 nna Hösel,2 and Ulrike Protzer1*

Institute of Virology, Technische Universität München/Helmholtz Zentrum München,

Trogerstr. 30, D-81675 Munich, Germany,1 Center for Molecular Medicine Cologne

(ZMMK), Institute for Medical Microbiology, Immunology, and Hygiene, University

of Cologne, f Stelzmann Str. 19-21, D-50935 Koeln, Germany2

Received 26 March 2010/ Accepted 10 August 2010

Apoptosis of infected cells is critically involved in antiviral defense.

Apoptosis, however, may also support the release and spread of viruses. Although

the elimination of infected hepatocytes is required to combat hepatitis B virus

(HBV) infection, it is still unknown which consequences hepatocyte apoptosis has

for the virus and whether or not it is advantageous to the virus. To study this,

we designed a cell culture model consisting of both HBV-producing cell lines and

primary human hepatocytes serving as an infection model. We showed that the

release of mature, enveloped virions was 80% to 90% reduced 24 h after the

induction of apoptosis in HBV-replicating hepatoma cells or HBV-infected

hepatocytes. Importantly, HBV particles released from apoptotic hepatocytes were

immature and nonenveloped and proved not to be infectious. We found an inverse

correlation between the strength of an apoptotic stimulus and the infectivity of

the virus particles released: the more potent the apoptotic stimulus, the higher

the ratio of nonenveloped capsids to virions and the lower their infectivity.

Furthermore, we demonstrated that HBV replication and, particularly, the

expression of the HBx protein transcribed from the viral genome during

replication do not sensitize cells to apoptosis. Our data clearly reject the

hypothesis that the apoptosis of infected hepatocytes facilitates the

propagation of HBV. Rather, these data indicate that HBV needs to prevent the

apoptosis of its host hepatocyte to ensure the release of infectious progeny

and, thus, virus spread in the liver.

--------------------------------------------------------------------------------

* Corresponding author. Mailing address: Institute of Virology Technische,

Universität München/Helmholtz Zentrum München, Trogerstr. 30, D-81675 München,

Germany. Phone: 49-89-41406821. Fax: 49-89-41406823. E-mail: protzer@...