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

在急性HIV-1感染中，妇女比男子更好地控制病毒复制。相比之下，女性在未经治疗的慢性HIV-1感染期间免疫激活增加，CD 4 + T细胞损失更快。越来越多的数据表明，HIV-1疾病表现的性别差异是由抗病毒免疫的性别特异性差异介导的。在以前的研究中，我们证明了来自女性的pDC比来自男性的pDC产生更多的IFNα以响应HIV-1，这可能有助于更好地控制急性感染中的病毒血症。然而，这种对HIV-1应答的IFNα产生的增加也导致慢性HIV-1感染妇女的免疫激活显著增加和CD 4 + T细胞的快速丧失。总之，这些数据有力地表明，I型IFN生产的性别差异导致女性和男性之间的HIV-1疾病表现的差异。然而，对HIV-1和其他传染病中这些性别差异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IFN应答中起关键作用，并且以HIV-1为模型，从X染色体失活（XCI）逃逸导致的基因剂量效应有助于抗病毒免疫的性别特异性差异。我们将进一步测试性激素水平的变化可以调节pDC的I型IFN应答的假设，使用来自人类跨性别队列的纵向样本。总之，这些研究将确定抗病毒免疫中性别特异性差异的关键机制，并为考虑女性和男性之间这些差异的干预措施设计提供理论依据。

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.