Type I IFN-mediated sex differences in immune responses to HIV-1

I 型 IFN 介导的 HIV-1 免疫反应中的性别差异

• 批准号: 453860923
• 负责人: Professor Dr. Marcus Altfeld
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/453860923?language=en
• 关键词: Type; IFN; mediated; sex; differences

In acute HIV-1 infection, women control viral replication better than men. In contrast, women develop increased immune activation and faster loss of CD4+ T cells during untreated chronic HIV-1 infection. Increasing data indicate that these sex differences in the manifestation of HIV-1 disease are mediated by sex-specific differences in antiviral immunity. In previous studies we demonstrated that pDCs derived from women produce more IFNα in response to HIV-1 than pDCs from men, potentially contributing to the better control of viremia in acute infection. This increased IFNα production in response to HIV-1 however also led to significantly higher immune activation and faster loss of CD4+ T cells in chronically HIV-1-infected women. Taken together these data strongly suggest that sex differences in Type I IFN production result in differences in HIV-1 disease manifestations between women and men. However, the precise molecular mechanisms underlying these sex differences in HIV-1 and other infectious diseases remain poorly understood. We hypothesize that X chromosome-encoded genes play a critical role in regulating Type I IFN responses, and that gene-dose effects resulting from escape from X chromosome inactivation (XCI) contribute to sex-specific differences in antiviral immunity, using HIV-1 as a model. We will furthermore test the hypothesis that changes in levels of sex hormones can regulate Type I IFN responses of pDCs, using longitudinal samples from a human transgender cohort. Taken together, these studies will identify critical mechanisms underlying sex-specific differences in antiviral immunity, and provide rationale for the design of interventions that take these differences between women and men into account.

在急性HIV-1感染中，女性比男性更好地控制病毒复制。相比之下，在未经治疗的慢性HIV-1感染期间，女性的免疫活性增强，CD4+T细胞损失更快。越来越多的数据表明，这些性别差异在HIV-1疾病的表现中是由抗病毒免疫的性别差异所介导的。在以前的研究中，我们证明了女性来源的pDC比男性来源的pDC产生更多的干扰素α，这可能有助于更好地控制急性感染中的病毒血症。然而，这增加了对艾滋病毒-1的反应的干扰素α的产生，也导致了慢性艾滋病毒-1感染妇女显著更高的免疫活性和更快的CD+T细胞损失。综上所述，这些数据强烈表明，I型干扰素产生的性别差异导致了艾滋病毒-1疾病在女性和男性之间的不同表现。然而，HIV-1和其他传染病中这些性别差异背后的确切分子机制仍然知之甚少。我们假设X染色体编码的基因在调节I型干扰素应答中起关键作用，并且以HIV-1为模型，X染色体失活(XCI)逃逸所产生的基因剂量效应有助于抗病毒免疫的性别差异。我们将进一步使用来自人类变性人队列的纵向样本，进一步检验性激素水平的变化可以调节pDC的I型干扰素反应的假设。综上所述，这些研究将确定性别差异在抗病毒免疫中的关键机制，并为考虑到男性和女性之间的这些差异的干预措施的设计提供理论基础。