AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
J Clin Invest. 2013 Jun;123(6):2629-42. doi: 10.1172/JCI64704. Epub 2013 May 1.
Viral vector-based vaccines that induce protective CD8+ T cell immunity can prevent or control pathogenic SIV infections, but issues of preexisting immunity and safety have impeded their implementation in HIV-1. Here, we report the development of what we believe to be a novel antigen-targeting DNA vaccine strategy that exploits the binding of programmed death-1 (PD1) to its ligands expressed on dendritic cells (DCs) by fusing soluble PD1 with HIV-1 GAG p24 antigen. As compared with non-DC-targeting vaccines, intramuscular immunization via electroporation (EP) of the fusion DNA in mice elicited consistently high frequencies of GAG-specific, broadly reactive, polyfunctional, long-lived, and cytotoxic CD8+ T cells and robust anti-GAG antibody titers. Vaccination conferred remarkable protection against mucosal challenge with vaccinia GAG viruses. Soluble PD1-based vaccination potentiated CD8+ T cell responses by enhancing antigen binding and uptake in DCs and activation in the draining lymph node. It also increased IL-12-producing DCs and engaged antigen cross-presentation when compared with anti-DEC205 antibody-mediated DC targeting. The high frequency of durable and protective GAG-specific CD8+ T cell immunity induced by soluble PD1-based vaccination suggests that PD1-based DNA vaccines could potentially be used against HIV-1 and other pathogens.
基于病毒载体的疫苗可以诱导保护性 CD8+ T 细胞免疫，从而预防或控制致病性 SIV 感染，但由于存在预先存在的免疫和安全性问题，它们在 HIV-1 中的应用受到了阻碍。在这里，我们报告了一种新型抗原靶向 DNA 疫苗策略的开发，该策略利用程序性死亡受体-1（PD1）与其在树突状细胞（DC）上表达的配体的结合，通过将可溶性 PD1 与 HIV-1 GAG p24 抗原融合来实现。与非 DC 靶向疫苗相比，通过电穿孔（EP）在小鼠中肌内免疫融合 DNA，可 consistently 地诱导高频率的 GAG 特异性、广泛反应性、多功能、长寿和细胞毒性 CD8+ T 细胞和强大的抗 GAG 抗体滴度。接种疫苗可显著保护免受痘苗 GAG 病毒的粘膜攻击。与抗 DEC205 抗体介导的 DC 靶向相比，可溶性 PD1 疫苗通过增强抗原在 DC 中的结合和摄取以及在引流淋巴结中的激活，增强了 CD8+ T 细胞反应。它还增加了产生 IL-12 的 DC，并参与了抗原交叉呈递。基于可溶性 PD1 的疫苗诱导的高频率持久和保护性 GAG 特异性 CD8+ T 细胞免疫表明，基于 PD1 的 DNA 疫苗可能可用于对抗 HIV-1 和其他病原体。
