Role of IFNe in immune modulation and HIV infection

项目摘要 干扰素e(Ifne)是保护宿主免受性传播的一种重要的先天免疫介质。 感染。虽然目前的范例是干扰素ε是一种I型干扰素，并通过干扰素受体传递信号，但我们的 和其他已发表的结果表明，干扰素ε具有独特的免疫功能，不同于干扰素/b。干扰素ε是 在雌性生殖道的粘膜中高度丰富，并具有优越的粘膜免疫活性 与IFNA/b相比，IFNe基因的表达受雌激素、细胞因子和精浆的调节，但不受 由Toll样受体通路诱导，从而诱导IFNA/b。临床证据表明， 抗艾滋病毒的IFNe。IFNe的表达与月经周期的雌激素水平呈正相关，并且 与艾滋病毒易感性呈负相关。重要的是，艾滋病毒阴性的性工作者经常接触 精液中IFNe基因表达水平升高，免疫效应物数量增加。 宫颈组织中的细胞。我们最近证明，IFNe通过一种机制诱导抗HIV状态 不依赖已知的I型干扰素诱导的原代巨噬细胞中的HIV宿主限制因子。另外， 干扰素ε可引起比干扰素2更强的免疫反应。我们假设IFNe在 通过保护HIV靶细胞和调节免疫功能来抑制HIV，并将检验我们的假设 通过体外培养、宫颈组织培养、宫颈组织培养和体外培养，研究IFNe的免疫机制及其对HIV感染的影响。 人性化的小鼠模型。为了更好地了解IFNe介导的HIV的分子机制 为了抑制，我们确定了对IFNe敏感性重要的病毒决定因素。因为众所周知，雌激素可以 调节IFNe表达和粘膜免疫，我们将评估雌激素对ε介导的干扰素的影响 绝经后妇女雌激素治疗前后HIV感染的过程。澄清 IFNe的性质和功能有望扩大我们对艾滋病毒至关重要的病毒与宿主相互作用的知识 预防和控制病毒库和免疫发病机制。

Project Summary Interferon e (IFNe) is a critical innate immune mediator that protects the host against sexually transmitted infections. Although the current paradigm is that IFNε is a type I IFN and signals through IFNa receptors, our and other published results show that IFNε has unique immune functions that are distinct from IFNa/b. IFNε is highly abundant in the mucosa of the female reproductive tract, and has superior mucosal immune activity compared to IFNa/b. IFNe gene expression is regulated by estrogen, cytokines, and seminal plasma, but is not induced by Toll-like receptor pathways, which induce IFNa/b. Clinical evidence indicates a protective role of IFNe against HIV. IFNe expression is positively associated with estrogen levels during the menstrual cycle, and inversely correlates with HIV susceptibility. Importantly, HIV-negative sex workers with frequent exposure to semen have an increased level of IFNe gene expression, and have increased numbers of immune effector cells in cervical tissues. We recently demonstrate that IFNe induces an anti-HIV state through a mechanism independent of known type I IFN-induced HIV host restriction factors in primary macrophages. Additionally, IFNε elicits a more robust immune response than IFNa2. We hypothesize is that IFNe displays a dual role in HIV inhibition by protecting HIV target cells and by modulating immune functions, and will test our hypothesis by determining the immune mechanism of IFNe and its impact on HIV infection in vitro, cervical explants and in humanized mouse model. To gain a better understanding of the molecular mechanism of IFNe-mediated HIV inhibition, we determine viral determinants important for IFNe sensitivity. Because estrogen is known to modulate IFNe expression and mucosal immunity, we will assess the impact of estrogen on IFNε-mediated processes in HIV infection in postmenopausal women before and after estrogen treatment. Elucidating the properties and functions of IFNe promises to expand our knowledge of virus-host interactions crucial for HIV prevention and control of viral reservoirs and immunopathogenesis.