CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge
CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge
复制标题
DOI：
10.1128/jvi.00975-14
复制
发表时间：
2014-09-01
影响因子：
5.4
通讯作者：
Amara, Rama Rao
中科院分区：
文献类型：
--
作者：
Kwa, Suefen;Lai, Lilin;Amara, Rama Rao
开发一种成功的能够预防感染的人类免疫缺陷病毒(HIV)疫苗仍然是一个挑战。在这里，我们利用CD40L的好处，作为我们的恒河猴免疫缺陷病毒(SIV)DNA疫苗的佐剂，CD40L是一种可以刺激树突状细胞(DC)和B细胞的共刺激分子。我们将CD40L与DNA/SIV疫苗共表达，使CD40L锚定在SIV病毒样颗粒(VLP)的膜上。这些含有SIV的CD40L VLP在体外对DC具有增强的激活作用。然后，我们测试了DNA/SIV-CD40L疫苗在恒河猴体内佐剂DNA/改良痘苗病毒安卡拉(MVA)疫苗的潜力。我们的结果表明，CD40L佐剂提高了抗Env抗体应答的功能质量和抗SIV CD8和CD4T细胞应答的广度，显著延迟了异种黏膜SIV感染的获得，改善了病毒控制。值得注意的是，CD40L佐剂增强了对挑战部位肠道病毒复制的控制，这与粘膜CD8免疫激活降低有关，CD8免疫激活是疾病进展的有力预测因素之一。总而言之，我们的结果突出了CD40L佐剂在增强抗病毒体液和细胞免疫方面的好处，从而增强了对致病性SIV的保护。同时增强体液和细胞免疫的单一佐剂是罕见的，因此CD40L作为包括HIV-1在内的传染病疫苗的佐剂的重要性和实用性。尽管艾滋病研究领域取得了许多进展，但能够预防感染的有效艾滋病疫苗仍然难以找到。CD40L是树突状细胞和B细胞的关键刺激因子，因此可以增强T细胞和抗体反应，但其过于强大的性质可能会导致不良反应，除非使用小剂量。为了在相对较低的水平上调节CD40L的局部表达，我们在核酸(DNA)载体中以膜结合的形式与SIV抗原一起表达了CD40L。我们利用异源黏膜SIV感染猕猴，测试了CD40L佐剂疫苗在猕猴体内的免疫原性和效果。CD40L佐剂疫苗提高了抗Env抗体应答的功能质量和抗SIV T细胞应答的广度，并改善了保护作用。这些结果表明，VLP膜结合的CD40L是一种新型的HIV疫苗佐剂。
It remains a challenge to develop a successful human immunodeficiency virus (HIV) vaccine that is capable of preventing infection. Here, we utilized the benefits of CD40L, a costimulatory molecule that can stimulate both dendritic cells (DCs) and B cells, as an adjuvant for our simian immunodeficiency virus (SIV) DNA vaccine in rhesus macaques. We coexpressed the CD40L with our DNA/SIV vaccine such that the CD40L is anchored on the membrane of SIV virus-like particle (VLP). These CD40L containing SIV VLPs showed enhanced activation of DCs in vitro. We then tested the potential of DNA/SIV-CD40L vaccine to adjuvant the DNA prime of a DNA/modified vaccinia virus Ankara (MVA) vaccine in rhesus macaques. Our results demonstrated that the CD40L adjuvant enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV CD8 and CD4 T cell responses, significantly delayed the acquisition of heterologous mucosal SIV infection, and improved viral control. Notably, the CD40L adjuvant enhanced the control of viral replication in the gut at the site of challenge that was associated with lower mucosal CD8 immune activation, one of the strong predictors of disease progression. Collectively, our results highlight the benefits of CD40L adjuvant for enhancing antiviral humoral and cellular immunity, leading to enhanced protection against a pathogenic SIV. A single adjuvant that enhances both humoral and cellular immunity is rare and thus underlines the importance and practicality of CD40L as an adjuvant for vaccines against infectious diseases, including HIV-1.IMPORTANCEDespite many advances in the field of AIDS research, an effective AIDS vaccine that can prevent infection remains elusive. CD40L is a key stimulator of dendritic cells and B cells and can therefore enhance T cell and antibody responses, but its overly potent nature can lead to adverse effects unless used in small doses. In order to modulate local expression of CD40L at relatively lower levels, we expressed CD40L in a membrane-bound form, along with SIV antigens, in a nucleic acid (DNA) vector. We tested the immunogenicity and efficacy of the CD40L-adjuvanted vaccine in macaques using a heterologous mucosal SIV infection. The CD40L-adjuvanted vaccine enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV T cell responses and improved protection. These results demonstrate that VLP-membrane-bound CD40L serves as a novel adjuvant for an HIV vaccine.