Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected Children on Combined Therapy

[Guest guest]

http://jvi.asm.org/cgi/content/abstract/85/5/2416

Journal of Virology, March 2011, p. 2416-2428, Vol. 85, No. 5

0022-538X/11/$012.00+0 doi:10.1128/JVI.01449-10

Copyright © 2011, American Society for Microbiology. .

Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen

Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected

Children on Combined Therapy

Ivana Carey,1 Lorenzo D'Antiga,1 Sanjay Bansal,1 Serena Longhi,1 Yun Ma,1

Irene Rebollo Mesa,2 Giorgina Mieli-Vergani,1 and Diego Vergani1*

Institute of Liver Studies and Paediatric Liver Centre, King's College London

School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS,

United Kingdom,1 MRC Centre for Transplantation, King's College London School of

Medicine at Guy's Hospital, St. Street, London, SE1 9RT, United Kingdom2

Received 12 July 2010/ Accepted 2 December 2010

The aim of the study was to investigate longitudinally hepatitis B virus

(HBV)-specific T-cell reactivity and viral behavior versus treatment response in

tolerant children during combined antiviral therapy. Twenty-three children with

infancy-acquired hepatitis B (HBeAg+) belonging to a published pilot study of

1-year treatment with lamivudine/alpha interferon (IFN-) were investigated. Five

seroconverted to anti-HBs (responders). Nine were HLA-A2+ (4 responders and 5

nonresponders). Mutations within the HBV core gene were determined at baseline

in liver and in serial serum samples by direct sequencing at baseline; during

treatment week 2 (TW2), TW9, TW28, and TW52; and after follow-up week 24 (FUW24)

and FUW52. HBV-specific reactivity was evaluated by T-cell proliferation with 16

HBV core 20-mer overlapping peptides and by HLA-A2-restricted core18-27 pentamer

staining and CD8+ IFN- enzyme-linked immunospot (ELISPOT) assay. HBV

core-specific T-cell proliferative and CD8 responses were more vigorous and

broader among responders than among nonresponders at TW28 and TW52, while the

number of mutations within HBV core gene immunodominant epitopes was lower at

TW28 and was negatively associated with HBV-specific T-cell proliferative

responses at both time points. The HBV DNA viral load was negatively associated

with HBV-specific T-cell proliferative and CD8 responses during treatment,

especially at TW28. Treatment-induced transition from immunotolerance to HBV

immune control is characterized by the emergence of efficient virus-specific

immune responses capable of restraining mutations and preventing viral evasion.

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

* Corresponding author. Mailing address: Institute of Liver Studies, King's

College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Phone: 44 20

32993305. Fax: 44 20 32993700. E-mail: diego.vergani@...

Published ahead of print on 8 December 2010.

[Guest guest]

http://jvi.asm.org/cgi/content/abstract/85/5/2416

Journal of Virology, March 2011, p. 2416-2428, Vol. 85, No. 5

0022-538X/11/$012.00+0 doi:10.1128/JVI.01449-10

Copyright © 2011, American Society for Microbiology. .

Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen

Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected

Children on Combined Therapy

Ivana Carey,1 Lorenzo D'Antiga,1 Sanjay Bansal,1 Serena Longhi,1 Yun Ma,1

Irene Rebollo Mesa,2 Giorgina Mieli-Vergani,1 and Diego Vergani1*

Institute of Liver Studies and Paediatric Liver Centre, King's College London

School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS,

United Kingdom,1 MRC Centre for Transplantation, King's College London School of

Medicine at Guy's Hospital, St. Street, London, SE1 9RT, United Kingdom2

Received 12 July 2010/ Accepted 2 December 2010

The aim of the study was to investigate longitudinally hepatitis B virus

(HBV)-specific T-cell reactivity and viral behavior versus treatment response in

tolerant children during combined antiviral therapy. Twenty-three children with

infancy-acquired hepatitis B (HBeAg+) belonging to a published pilot study of

1-year treatment with lamivudine/alpha interferon (IFN-) were investigated. Five

seroconverted to anti-HBs (responders). Nine were HLA-A2+ (4 responders and 5

nonresponders). Mutations within the HBV core gene were determined at baseline

in liver and in serial serum samples by direct sequencing at baseline; during

treatment week 2 (TW2), TW9, TW28, and TW52; and after follow-up week 24 (FUW24)

and FUW52. HBV-specific reactivity was evaluated by T-cell proliferation with 16

HBV core 20-mer overlapping peptides and by HLA-A2-restricted core18-27 pentamer

staining and CD8+ IFN- enzyme-linked immunospot (ELISPOT) assay. HBV

core-specific T-cell proliferative and CD8 responses were more vigorous and

broader among responders than among nonresponders at TW28 and TW52, while the

number of mutations within HBV core gene immunodominant epitopes was lower at

TW28 and was negatively associated with HBV-specific T-cell proliferative

responses at both time points. The HBV DNA viral load was negatively associated

with HBV-specific T-cell proliferative and CD8 responses during treatment,

especially at TW28. Treatment-induced transition from immunotolerance to HBV

immune control is characterized by the emergence of efficient virus-specific

immune responses capable of restraining mutations and preventing viral evasion.

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

* Corresponding author. Mailing address: Institute of Liver Studies, King's

College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Phone: 44 20

32993305. Fax: 44 20 32993700. E-mail: diego.vergani@...

Published ahead of print on 8 December 2010.