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

摘要 以前，我们对来自美国的高危妇女进行了大规模的粘膜细胞因子和HIV感染的分析， 夸祖鲁-纳塔尔，南非，作为CAPRISA 004 TFV 1%凝胶研究的一部分入组（n = 774）。使用 前瞻性队列设计，我们验证了我们以前的发现，炎症细胞因子增加艾滋病毒的风险 采集在与风险增加相关的细胞因子中， 关键的I型IFN，IFN γ 2（p = 10 E-6）。IFN-γ 2水平上四分位数的女性， 艾滋病毒，与妇女相比处于最低四分位数（风险比3.9，95%置信区间1.7-9.1）。从表面上看，这似乎是反- 直观地，由于I型IFN在体外和作为治疗剂在体内给予时都具有强抗HIV作用， 在非人灵长类动物模型中预防。为了调和这些观察结果，我们假设慢性型 IFN在女性生殖道（FRT）中的上调导致IFN信号转导的失调，从而导致IFN-γ的表达增加。 抗病毒基因下调，全身炎症增加和易感性增加 感染部位的靶细胞。这一假设将提供一个解释，为什么一个经典的反 本应具有保护作用的病毒治疗项目实际上导致了更高的艾滋病感染率。利用来自 正在进行的CAPRISA 018替诺福韦艾拉酚胺（TAF）皮下植入试验，我们将确定是否 FRT中IFN β 2的长期上调导致IFN反应性降低和IFN刺激基因（ISG） 在生殖器免疫细胞中的表达。接下来，我们将正式测试IFN γ 2表达的慢性增加， ISG下调对应于CAPRISA 018中登记的年轻女性的突破性艾滋病毒感染。 最后，我们将使用体外PBMC模型来确定延长IFN上调的机制。 导致ISG下调和随后的HIV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.