Incorporation of CD40 Ligand into the Envelope of Pseudotyped Single-Cycle Simian Immunodeficiency Viruses Enhances Immunogenicity
Incorporation of CD40 Ligand into the Envelope of Pseudotyped Single-Cycle Simian Immunodeficiency Viruses Enhances Immunogenicity
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DOI：
10.1128/jvi.01870-08
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发表时间：
2009-02-01
影响因子：
5.4
通讯作者：
Yilma, Tilahun D.
中科院分区：
文献类型：
--
作者：
Lin, Fan-ching;Peng, Yue;Yilma, Tilahun D.
为了控制艾滋病的流行，迫切需要一种预防人类免疫缺陷病毒(HIV)感染的疫苗。为了解决这个问题，我们开发了水泡性口炎病毒糖蛋白伪型复制缺陷猴免疫缺陷病毒(DSIV)作为艾滋病疫苗策略。DSIV保留了减毒活病毒的特征，没有复制病毒造成的潜在毒力的缺点。为了提高疫苗的免疫原性，我们将CD40配体(CD40L)引入到dSIV包膜中。CD40L是促进树突状细胞(DC)成熟和激活的最有效的刺激因子之一。CD40L与其受体结合可上调DC表面主要组织相容性复合体I类、II类和共刺激分子的表达，增加致炎细胞因子和趋化因子的产生，尤其是IL-12。这种细胞因子将CD4(+)T细胞极化为Th1型免疫反应。通过DC活化和混合淋巴细胞反应(MLR)检测CD40L-dSIV的体外免疫原性。CD40L-dSIV转导的DC(CD40L-dSIV)的CD80、CD86、HLA-DR和CD54的表达水平明显高于转导dSIV的DC。此外，CD40L-dSIV转导的DC表达IL-12的量是转导dSIV的DC的10倍。CD40L-dSIV转导的DC在MLR中促进初始T细胞的增殖和γ干扰素的分泌。此外，CD40L-dSIV免疫小鼠表现出比dSIV免疫动物更强的体液免疫和细胞免疫应答。结果表明，在dSIV包膜中掺入CD40L可显著增强免疫原性。因此，CD40L-dSIV有可能成为开发安全、高免疫原性艾滋病疫苗的有力候选者。
A vaccine for the prevention of human immunodeficiency virus (HIV) infection is desperately needed to control the AIDS pandemic. To address this problem, we developed vesicular stomatitis virus glycoprotein-pseudotyped replication-defective simian immunodeficiency viruses (dSIVs) as an AIDS vaccine strategy. The dSIVs retain characteristics of a live attenuated virus without the drawbacks of potential virulence caused by replicating virus. To improve vaccine immunogenicity, we incorporated CD40 ligand (CD40L) into the dSIV envelope. CD40L is one of the most potent stimuli for dendritic cell (DC) maturation and activation. Binding of CD40L to its receptor upregulates expression of major histocompatibility complex class I, class II, and costimulatory molecules on DCs and increases production of proinflammatory cytokines and chemokines, especially interleukin 12 (IL-12). This cytokine polarizes CD4(+) T cells to Th1-type immune responses. DC activation and mixed lymphocyte reaction (MLR) studies were performed to evaluate the immunogenicity of CD40L-dSIV in vitro. Expression levels of CD80, CD86, HLA-DR, and CD54 on DCs transduced with the dSIV incorporating CD40L (CD40L-dSIV) were significantly higher than on those transduced with dSIV. Moreover, CD40L-dSIV-transduced DCs expressed up to 10-fold more IL-12 than dSIV-transduced DCs. CD40L-dSIV-transduced DCs enhanced proliferation and gamma interferon secretion by naive T cells in an MLR. In addition, CD40L-dSIV-immunized mice exhibited stronger humoral and cell-mediated immune responses than dSIV-vaccinated animals. The results show that incorporating CD40L into the dSIV envelope significantly enhances immunogenicity. As a result, CD40L-dSIVs can be strong candidates for development of a safe and highly immunogenic AIDS vaccine.