Ha Sang-Jun, West Erin E, Araki Koichi, Smith Kendall A, Ahmed Rafi
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Immunol Rev. 2008 Jun;223:317-33. doi: 10.1111/j.1600-065X.2008.00638.x.
One potentially promising strategy to control chronic infections such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus is therapeutic vaccination, which aims to reduce persisting virus by stimulating a patient's own antiviral immune responses. However, this approach has fallen short of expectations, because antiviral T cells generated during chronic infections often become functionally exhausted and thus do not respond properly to therapeutic vaccination. Therefore, it is necessary to develop a therapeutic vaccine strategy to more effectively boost endogenous T-cell responses to control persistent viral infections. Studies to elucidate the cause of impaired T-cell function have pointed to sustained inhibitory receptor signaling through T-cell expression of programmed death 1 (PD-1). Recently, another inhibitory molecule, cytotoxic T lymphocyte antigen 4 (CTLA-4), and also an immunosuppressive cytokine, interleukin 10 (IL-10), have been reported to be potential factors of establishing immune suppression and viral persistence. Blocking these negative signaling pathways could restore the host immune system, enabling it to respond to further stimulation. Indeed, combining therapeutic vaccination along with the blockade of inhibitory signals could synergistically enhance functional CD8(+) T-cell responses and improve viral control in chronically infected mice, providing a promising strategy for the treatment of chronic viral infections. Furthermore, not only the ablation of negative signals but also the addition of stimulatory signals, such as interleukin 2 (IL-2), might prove to be a potentially promising strategy to augment the efficacy of therapeutic vaccination against chronic viral infections.
一种控制慢性感染（如人类免疫缺陷病毒、乙型肝炎病毒和丙型肝炎病毒）的潜在有前景的策略是治疗性疫苗接种，其目的是通过刺激患者自身的抗病毒免疫反应来减少持续存在的病毒。然而，这种方法未达预期，因为慢性感染期间产生的抗病毒T细胞常常功能耗竭，因此对治疗性疫苗接种反应不佳。所以，有必要开发一种治疗性疫苗策略，以更有效地增强内源性T细胞反应，从而控制持续性病毒感染。阐明T细胞功能受损原因的研究指出，通过程序性死亡1（PD-1）在T细胞上的表达导致持续的抑制性受体信号传导。最近，另一种抑制分子细胞毒性T淋巴细胞抗原4（CTLA-4）以及一种免疫抑制细胞因子白细胞介素10（IL-10），被报道是建立免疫抑制和病毒持续存在的潜在因素。阻断这些负信号通路可恢复宿主免疫系统，使其能够对进一步刺激做出反应。确实，将治疗性疫苗接种与抑制性信号阻断相结合，可协同增强功能性CD8(+) T细胞反应，并改善慢性感染小鼠的病毒控制，为慢性病毒感染的治疗提供了一种有前景的策略。此外，不仅消除负信号，而且添加刺激性信号，如白细胞介素2（IL-2），可能被证明是增强治疗性疫苗接种对慢性病毒感染疗效的一种潜在有前景的策略。
