Mechanisms of type I IFN signaling and HIV risk in the female genital tract

摘要 此前，我们对高危妇女的粘膜细胞因子和艾滋病毒感染进行了大规模分析。 夸祖鲁-纳塔尔，南非，作为CAPRISA 004 TFV 1%凝胶研究的一部分(n=774)。使用 前瞻性队列设计，我们验证了我们之前的发现，炎性细胞因子增加了艾滋病毒的风险 收购。在与风险增加相关的细胞因子中，观察到的最强关联之一是 I型干扰素，干扰素2(p=10e-6)。处于干扰素2高四分位数的女性感染的风险是男性的4倍 与处于最低四分位数的妇女相比(HR 3.9，95%CI 1.7-9.1)。从表面上看，这似乎适得其反- 直觉上，I型干扰素在体外和体内都有很强的抗艾滋病毒作用，作为一种治疗性或 在非人类灵长类动物模型中进行预防。为了与这些观察结果相一致，我们假设慢性类型 I型干扰素在女性生殖道(FRT)的上调导致干扰素信号的失调，从而导致 在抗病毒基因下调中，全身性炎症增加和易感性增加 感染部位的靶细胞。这一假说将提供一种解释为什么一个经典的反 本应具有保护性的病毒计划实际上会导致更高的艾滋病毒获得率。利用来自以下方面的样本 正在进行的CAPRISA 018替诺福韦丙氨酰胺(TAF)皮下埋植试验，我们将确定 长期干扰素2上调导致干扰素反应性和干扰素刺激基因(Isg)下降 在生殖器免疫细胞中表达。接下来，我们将正式测试干扰素2表达的慢性增加和 ISG下调对应于CAPRISA 018中登记的年轻女性中艾滋病毒感染的突破性进展。 最后，我们将使用体外PBMC模型来确定延长干扰素上调的机制 导致ISG下调调控，随之而来的艾滋病毒风险增加。

ABSTRACT Previously, we carried out large-scale analysis of mucosal cytokines and HIV acquisition in high-risk women from KwaZulu-Natal, South Africa, enrolled as part of the CAPRISA 004 TFV 1% gel study (n = 774). Using a prospective cohort design, we validated our previous finding that inflammatory cytokines increase the risk of HIV acquisition. Of the cytokines associated with increased risk, one of the strongest associations was observed for the key type I IFN, IFN2 (p = 10E-6). Women in upper quartile for IFN2 were at 4-fold greater risk of acquiring HIV, compared to women in the lowest quartile (HR 3.9, 95% CI 1.7-9.1). On the surface this seems counter- intuitive, as type I IFN have strong anti-HIV effects both in vitro and when given in vivo as a therapeutic or prophylactic in non-human primate model. To reconcile these observations, we hypothesize that chronic type I IFN upregulation in the female reproductive tract (FRT) leads to dysregulation of IFN signaling, resulting in downregulation of antiviral genes, increase in generalized inflammation and increase in susceptibility of target cells at the site of infection. This hypothesis would provide an explanation as to why a classical anti- viral program that should be protective actually leads to higher rates of HIV acquisition. Utilizing samples from the ongoing CAPRISA 018 tenofovir alafenamide (TAF) sub-dermal implant trial, we will determine whether prolonged IFN2 upregulation in the FRT leads to decreased IFN responsiveness and IFN-stimulated gene (ISG) expression in genital immune cells. Next, we will formally test if the chronic increase in IFN2 expression and ISG downregulation correspond to breakthrough HIV infections in young women enrolled in CAPRISA 018. Finally, we will use an in vitro PBMC model to determine the mechanism by which prolonged IFN upregulation leads to ISG downregulation and subsequent increase in HIV risk.