HIV-1 T cell epitopes targeted to Rhesus macaque CD40 and DCIR: A comparative study of prototype dendritic cell targeting therapeutic vaccine candidates
HIV-1 T cell epitopes targeted to Rhesus macaque CD40 and DCIR: A comparative study of prototype dendritic cell targeting therapeutic vaccine candidates
复制标题
DOI：
10.1371/journal.pone.0207794
复制
发表时间：
2018-11-30
期刊：
影响因子：
3.7
通讯作者：
Levy, Yves
中科院分区：
文献类型：
--
作者：
Flamar, Anne-Laure;Bonnabau, Henri;Levy, Yves
HIV-1 感染可以通过抗逆转录病毒药物治疗来控制，但这是终生治疗，病毒仍处于潜伏状态，如果停止治疗，病毒会迅速反弹。接受这种药物治疗的 HIV-1 感染者由于免疫力受损，癌症、心血管疾病和自身免疫性疾病的发病率增加。因此，需要一种增强针对 HIV-1 的细胞免疫的治疗性疫苗，并且可能与其他免疫调节剂结合使用，从而无需长期药物治疗。引发基于 T 细胞的强大免疫力的一种方法是将病毒蛋白抗原特异性引导至树突状细胞 (DC)，树突状细胞是控制免疫反应的关键细胞类型。为了在 HIV-1 感染者中引发治疗性细胞免疫，我们开发了由 HIV-1 Gag、Nef 和 Pol (HIV5pep) 五个富含 T 细胞表位的区域组成的疫苗，这些区域与结合抗原呈递细胞激活受体 CD40 或内吞树突细胞免疫受体 DCIR 的单克隆抗体融合。该研究旨在证明疫苗的安全性，确定在初始环境和初始环境中广泛 T 细胞反应的功效，并确定一种用于人类治疗开发的候选疫苗。通过皮内注射聚 ICLC 佐剂将疫苗给予恒河猴。这些动物要么是 i) 未经处理的，要么 ii) 之前用编码 HIV-1 Gag、Pol 和 Nef (MVA GagPolNef) 的改良痘苗安卡拉载体 (MVA) 进行了引发。在MVA引发组中，两种DC靶向疫苗均增强了HIV5pep特异性血液CD4(+) T细胞产生多种细胞因子，但不影响MVA引发的CD8(+) T细胞反应。在初始组中，两种 DC 靶向疫苗均引发针对多个表位的抗原特异性多功能 CD4(+) 和 CD8(+) T 细胞反应，并且这些反应在随后的 MVA GagPolNef 加强后没有改变。在这两种情况下，通过 CD40 靶向疫苗引发的 T 细胞反应更加强劲，并且在所有动物中均可检测到，这有利于进一步开发用于 HIV-1 感染个体的治疗性疫苗接种的 CD40 靶向疫苗。
HIV-1 infection can be controlled by anti-retroviral drug therapy, but this is a lifetime treatment and the virus remains latent and rapidly rebounds if therapy is stopped. HIV-1-infected individuals under this drug regimen have increased rates of cancers, cardiovascular diseases, and autoimmunity due to compromised immunity. A therapeutic vaccine boosting cellular immunity against HIV-1 is therefore desirable and, possibly combined with other immune modulating agents, could obviate the need for long-term drug therapies. An approach to elicit strong T cell-based immunity is to direct virus protein antigens specifically to dendritic cells (DCs), which are the key cell type for controlling immune responses. For eliciting therapeutic cellular immunity in HIV-1-infected individuals, we developed vaccines comprised of five T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol (HIV5pep) fused to monoclonal antibodies that bind either, the antigen presenting cell activating receptor CD40, or the endocytic dendritic cell immunoreceptor DCIR. The study aimed to demonstrate vaccine safety, establish efficacy for broad T cell responses in both primed and naive settings, and identify one candidate vaccine for human therapeutic development. The vaccines were administered to Rhesus macaques by intradermal injection with poly-ICLC adjuvant. The animals were either i) naive or, ii) previously primed with modified vaccinia Ankara vector (MVA) encoding HIV-1 Gag, Pol, and Nef (MVA GagPolNef). In the MVA-primed groups, both DC-targeting vaccinations boosted HIV5pep-specific blood CD4(+) T cells producing multiple cytokines, but did not affect the MVA-elicited CD8(+) T cell responses. In the naive groups, both DC-targeting vaccines elicited antigen-specific polyfunctional CD4(+) and CD8(+) T cell responses to multiple epitopes and these responses were unchanged by a subsequent MVA GagPolNef boost. In both settings, the T cell responses elicited via the CD40-targeting vaccine were more robust and were detectable in all the animals, favoring further development of the CD40-targeting vaccine for therapeutic vaccination of HIV-1-infected individuals.