Lentivector expressing HBsAg and immunoglobulin Fc fusion antigen induces potent

StephenW

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 Michael Mi,5 David 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: [email protected] or Guiqiang
Wang, Department of Infectious Diseases, First Affiliated Hospital of
Peking University, Email: [email protected]

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, Collins 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.




(6.合.彩).足球.篮球...各类投注开户下注

第一投注.现金网:招代理年薪10万以上:6668.cc

StephenW

N.B. The full paper is available from the link.

My personal opinions about this paper:
1. Lentivector is a gene delivery method using the Lentivirus.
慢病毒屬                                                                                                                                        维基百科，自由的百科全书
                                                                                                                                                                                                                                                                                                                                                                                                                                慢病毒屬是反轉錄病毒科下的一個屬，此屬病毒的特徵是需要較長的時間才能培養出來，例如人類免疫缺陷病毒(HIV)、猴免疫缺陷病毒(SIV)、 貓免疫缺陷病毒(FIV)都是慢病毒屬，慢病毒屬的原文是Lentivirus，其中Lenti-在拉丁文中有慢的意思。
慢病毒屬可以由宿主細胞直接感染周圍的細胞，不必經由形成病毒顆粒此一步驟。
慢病毒感染non-cycling细胞。

2. The research is done on mice only.
3. The results seem to require low 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."
4. This seems to be a joint effort between Chinese and American scientists.

gujijungu

写了这么多。。就是没看懂。

StephenW

gujijungu 发表于 2011-8-22 17:46
写了这么多。。就是没看懂。

Try this:

In the study, we found that lentivector induced potent HBsAg specific CD8 T cell responses. IgG2a Fc fragment tagging further enhanced the HBsAg specific adaptive immunity including CD8, CD4 responses, and humoral responses. Importantly, lentivector immunization could induce immune responses in the HBsAg Tg mice with low level of HBsAg and decreased the HBsAg level to become negative in the mouse serum. Remarkably, lentivector immunization also converted the mice into anti-HBsAb positive, suggesting that it may be possible to break immune tolerance when the viral Ag load is low, which can be achievable by antiviral drugs in clinical setting. Thus, such immunotherapy has the potential of working together with antiviral therapy to establish the immune responses to control HBV infection. Further investigations are warranted to explore this potential.

在这项研究中，我们发现，lentivector引起的烈性乙肝表面抗原特异性CD8 T细胞反应。 IgG2a Fc片段标签进一步增强包括CD8 + HBsAg的具体适应性免疫，CD4 +反应，体液免疫应答。更重要的是，lentivector免疫能诱导低水平的HBsAg乙肝表面抗原的Tg小鼠的免疫反应，并成为负鼠血清HBsAg水平下降。值得注意的是，lentivector免疫也转换成抗乙肝表面抗体阳性小鼠，暗示，它可能会打破免疫耐受，当病毒抗原负荷低，抗病毒药物在临床上可实现的。因此，这种免疫治疗的抗病毒药物治疗工作，建立控制HBV感染的免疫反应的潜力。进一步调查是必要的，以探讨这一潜力。

写电子邮件到这两个中国的研究人员以取得解释。
Corresponding address: Yukai He, Immunology/Immunotherapy Program, MCG Cancer Center, Medical College of Georgia,
Email: [email protected] or Guiqiang Wang, Department of Infectious Diseases, First Affiliated Hospital of Peking University,
Email: [email protected]

走遍四方

慢病毒？

StephenW

走遍四方 发表于 2011-8-23 10:15
慢病毒？

An experimental therapeutic DNA vaccine that seems to work in mice model of hbv.
[My opinion only]

上海人

你怎么叫四蹄?

StephenW

上海人 发表于 2011-8-23 23:27
你怎么叫四蹄?

Stephen -->斯蒂芬--(老王) -->四蹄芬