Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells

Humans infected with yellow fever virus (YFV), a mosquito-borne flavivirus, can develop illness ranging from a mild febrile disease to hemorrhagic fever and death. The 17D vaccine strain of YFV was developed in the 1930s, has been used continuously since development and has proven very effective. Genetic differences between vaccine and wild-type viruses are few, yet viral or host mechanisms associated with protection or disease are not fully understood. Over the past 20 years, a number of cases of vaccine-associated disease have been identified following vaccination with 17D; these cases have been correlated with reduced immune status at the time of vaccination. Recently, several studies have evaluated T cell responses to vaccination in both humans and non-human primates, but none have evaluated the response to wild-type virus infection. In the studies described here, monocyte-derived macrophages (MDM) and dendritic cells (MoDC) from both humans and rhesus macaques were evaluated for their ability to support infection with either wild-type Asibi virus or the 17D vaccine strain and the host cytokine and chemokine response characterized. Human MoDC and MDM were also evaluated for their ability to stimulate CD4+ T cells. It was found that MoDC and MDM supported viral replication and that there were differential cytokine responses to infection with either wild-type or vaccine viruses. Additionally, MoDCs infected with live 17D virus were able to stimulate IFN-γ and IL-2 production in CD4+ T cells, while cells infected with Asibi virus were not. These data demonstrate that wild-type and vaccine YFV stimulate different responses in target antigen presenting cells and that wild-type YFV can inhibit MoDC activation of CD4+ T cells, a critical component in development of protective immunity. These data provide initial, but critical insight into regulatory capabilities of wild-type YFV in development of disease.

感染黄热病毒（Yellow Fever Virus, YFV）——一种虫媒黄病毒的人类感染者，可出现从轻症发热性疾病到出血热乃至死亡的多样临床表型。YFV的17D疫苗株于1930年代研发成功，自问世以来持续应用至今，且已被证实具备极高的保护效力。尽管疫苗株与野生型病毒的遗传差异微乎其微，但与保护性免疫或疾病发生相关的病毒及宿主调控机制仍未完全阐明。
近二十年来，多例接种17D疫苗后出现疫苗相关疾病的病例被陆续报道，此类病例与接种时宿主免疫状态低下存在显著相关性。近期已有多项研究针对人类与非人灵长类动物的疫苗接种后T细胞应答展开评估，但尚无研究探讨野生型YFV感染后的宿主应答情况。
本研究中，研究人员对人类与恒河猴来源的单核细胞衍生巨噬细胞（monocyte-derived macrophages, MDM）及单核细胞衍生树突状细胞（monocyte-derived dendritic cells, MoDC）支持野生型Asibi病毒或17D疫苗株感染的能力，以及宿主的细胞因子与趋化因子应答特征进行了系统性评估。同时，本研究还检测了人类MoDC与MDM刺激CD4阳性T细胞的功能。
实验结果显示，MoDC与MDM均可支持病毒复制，且针对野生型病毒与疫苗株病毒的感染，宿主呈现出差异化的细胞因子应答谱。此外，感染活17D疫苗株的MoDC可诱导CD4阳性T细胞产生干扰素γ（IFN-γ）与白细胞介素2（IL-2），而感染Asibi野生型病毒的MoDC则无此效应。
上述数据表明，野生型与疫苗株YFV可在靶抗原呈递细胞中诱导截然不同的免疫应答，且野生型YFV能够抑制MoDC对CD4阳性T细胞的激活——这一过程是保护性免疫建立过程中的关键环节。本研究为野生型YFV在疾病发生过程中的调控能力提供了初步但至关重要的科学认知。