Lentivector expressing HBsAg and immunoglobulin Fc fusion antigen induces potent immune responses and results in seroconversion in HBsAg transgenic mice

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FULL TEXT: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090480/

Vaccine. Author manuscript; available in PMC 2011 July 17.

Published in final edited form as:

Vaccine. 2011 May 17; 29(22): 3909–3916.

Published online 2011 March 21. doi: 10.1016/j.vaccine.2011.03.025

PMCID: PMC3090480

NIHMSID: NIHMS278877

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Lentivector expressing HBsAg and immunoglobulin Fc fusion antigen induces potent

immune responses and results in seroconversion in HBsAg transgenic mice*

Yuan Hong,1,4 Yibing Peng,1 Mi,5 H Munn,1,3 Gui-qiang Wang,4 and

Yukai He1,2

1Immunology/Immunotherapy Program, MCG Cancer Center, Georgia Health Science

University, Augusta, GA

2Department of Medicine, Georgia Health Science University, Augusta, GA

3Department of Pediatrics, Georgia Health Science University, Augusta, GA

4Department of Infectious Diseases, Peking University First Hospital, Beijing,

China

5Harvard College, Harvard University, Boston, MA

Corresponding address: Yukai He, Immunology/Immunotherapy Program, MCG Cancer

Center, Medical College of Georgia, Email: yhe@... or Guiqiang Wang,

Department of Infectious Diseases, First Affiliated Hospital of Peking

University, Email: wanggq@...

The publisher's final edited version of this article is available at Vaccine

Abstract

Even though hepatitis B virus (HBV) vaccines effectively prevent new cases of

HBV infection, with approximately 350 million patients worldwide, chronic HBV

infection remains a major health problem because of the associated complications

(such as liver cirrhosis and hepatocellular carcinoma) and the limited treatment

options. Immunotherapy has the potential to effectively control HBV replication.

In this current study, we found that recombinant lentivectors could induce

potent HBV surface antigen (HBsAg) specific T cell responses and humoral immune

responses. Tagging the HBsAg with immunoglobulin Fc fragment further

substantially increased the HBsAg specific immune responses. Remarkably, the

HBS-Fc-lv lentivector could effectively break immune tolerance and induce potent

HBsAg specific adaptive immune responses in HBsAg transgenic (Tg) mice with low

serum level of HBsAg. More importantly, the induction of HBsAg specific immune

responses in Tg mice accompanied seroconversion from HBsAg to anti-HBsAg

antibody (anti-HBsAb). Our study demonstrated the potential of utilizing

lentivector to treat chronic HBV infection following reduction of viral load

with antiviral drug therapy.

1. Introduction

Wide application of protein based hepatitis B virus (HBV) vaccines has been

successful in preventing new cases of HBV infections [1]. However, for more than

350 millions of chronic carriers who have already been infected with HBV, the

treatment options are limited. Interferon is effective only in a small

proportion of chronic HBV patients. Nucleoside and nucleotide analogue antiviral

drugs are only virostatic rather viricidal, and their use is limited by the

life-long dependence on these drugs, the risk of emerging drug resistant viruses

[2], and side effects [3]. Chronic HBV infection without treatment can lead to

severe liver diseases including liver cirrhosis and hepatocellular carcinoma.

The idea of utilizing immunotherapy to control HBV replication is supported by

findings that patients who recovered from acute HBV infections usually contained

high levels of polyclonal T cell responses against multiple HBV Ags [4–5] and

that bone marrow transplantation of anti-HBV immunity to recipient could cure

chronic HBV infections [6]. Prophylactic HBV vaccines and dendritic cell (DC)

based vaccines have been examined for their potential to treat chronic HBV

infection [7–8]. Even though they are well tolerated in chronic HBV patients,

their effectiveness remains limited. DNA based HBV vaccines were found to be

capable of eliciting CD8 T cell responses in one animal model [9], but they

failed to break immune tolerance in another HBV transgenic (Tg) mouse model

[10]. Although DC based vaccine could break tolerance and induce immune

responses in Tg mice [10–11], their effect on converting the HBV serum markers

was not certain, possibly because the magnitude of immune responses was low

[10]. In clinical trial, the protein and DNA based immunotherapy of chronic HBV

infection were found not to be effective [7, 12–14]. Thus, there is a need to

develop more potent immunization approaches for the purpose of treating chronic

HBV infection.

We and others previously found that recombinant lentivectors could induce potent

T cell immunity against self tumor Ag and model Ag [15–18] possibly because they

can effectively transduce DCs and directly prime naïve T cells by skin derived

DCs in vivo [19–21]. Lentivector immunization stimulates much higher CD8 T cell

immune responses than DNA vaccines and other viral vectors [19]. Recently,

and colleagues demonstrated that non-integrating lentivector

immunization could effectively stimulate anti-HBs antibody (Ab) in the

circulation and T cell responses in naïve mice [22]. However, no attempt was

made to study if lentivector could be also effective in the presence of HBsAg

and if such immune responses could result in therapeutic benefits.

Therefore, in the current study, we investigated the potential of lentivector

immunization to induce HBV surface (HBs) Ag specific immune responses and

whether lentivector immunization can break tolerance to induce HBsAg specific

immune responses in HBsAg Tg mice. We found that lentivector immunization

elicited potent HBsAg specific CD8 T cell responses. Furthermore, tagging HBsAg

with immunoglobulin (Ig) Fc fragment markedly enhanced CD8 immune responses and

stimulated CD4 T cell responses and anti-HBsAb. Importantly, lentivector

immunization also induced HBsAg specific adaptive immune responses in the Tg

mice expressing low level of HBsAg even though failed to break tolerance in the

Tg mice with high level of HBsAg. Our data suggest that lentivector expressing

Fc tagged HBsAg is a potent immunization vehicle for stimulating HBsAg specific

adaptive immune responses and may be capable of inducing HBsAg specific immune

responses in the presence of low level of HBsAg, implicating the potential of

using lentivector for immunotherapy of chronic HBV infection following reducing

the viral antigen load with antiviral treatment.