Role of Type I IFNs in Mucosal HIV-1 Immunity and Pathogenesis

摘要 肠道是早期HIV-1感染和CD4+T细胞耗尽的主要部位，也是 I型干扰素的抗病毒作用，包括12种干扰素α亚型和干扰素β。然而，最初的 干扰素的反应可能不是最理想的，因为传播/方正(Tf)HIV-1毒株仍能设法突破。 利用下一代测序技术，我们报道了由浆细胞样树突状细胞表达的干扰素α亚型 体外暴露HIV-1后的细胞(PDCs)具有相对较弱的抗病毒活性。这些微弱的抗病毒干扰素α 亚型包括干扰素α2，唯一获准临床使用的干扰素α亚型，以及干扰素α1，潜在的干扰素拮抗剂 I型干扰素信号。到目前为止，对干扰素α亚型的调节和生物学特性的深入研究 而干扰素β在原代pDC和肠道细胞中的表达尚未得到证实。矛盾的是，I型IFN也是 与慢性免疫激活有关，这是艾滋病毒-1疾病进展的有力预测因素。表型很可能是 由于I型IFN的免疫调节特性，但确切的机制尚不清楚。值得注意的是， 肠道屏障功能障碍在HIV-1感染早期发生，导致微生物移位到板层 专有物，导致免疫激活。我们报告了革兰氏阴性共生菌在 HIV-1感染者肠道黏膜促进肠道内HIV-1复制和CD4+T细胞体外死亡 Propra层聚集培养(LPAC)模型。在这里，我们假设从一个 I型IFN对致病作用的保护作用可能是通过转移肠道微生物来驱动的。 微生物暴露可能会提高I型干扰素的抗病毒作用的门槛，使之显露并获得许可。 免疫调节ISGs促进髓系(MDC)活化/转感染和CD4+T细胞感染/ 细胞凋亡。I型IFN的这些微生物驱动的致病作用可能在慢性感染期间持续存在。 有趣的是，我们观察到慢性HIV-1感染期间的I型干扰素反应在 体内，分别在血液和肠道中使用差异增强的干扰素α和干扰素β。到目前为止， 肠道中I型干扰素信号升高的细胞来源和机制尚不清楚。我们 因此建议研究I型干扰素在肠道HIV-1感染中的作用 微生物移位，并在慢性期。在目标1中，我们将评估抗HIV-1的调节 干扰素α亚型和干扰素β的活性和功能性质。在目标2中，我们将确定I型IFN如何 在HIV-1相关的肠道生物失调和死亡的背景下调节MDC激活和T细胞功能/存活 微生物易位。在目标3中，我们将确定异常I型干扰素签名的来源和触发因素 在慢性感染期间使用未感染、未治疗的HIV-1感染和HIV-1抑制的肠道组织 个人。这些结果应该为I型IFN如何影响HIV-1的致病机制提供迫切需要的见解 这可能会提供策略，要么利用这些抗病毒细胞因子进行治疗，要么阻止它们 免疫作用，减轻慢性炎症。

ABSTRACT The gut is a major site for early HIV-1 infection and CD4+ T cell depletion, and a critical compartment for the antiviral action of the type I interferons (IFN) that include the 12 IFNα subtypes and IFNβ. However, the initial IFN response may be suboptimal, as transmitted/founder (TF) HIV-1 strains still manage to break through. Using next-generation sequencing, we reported that the IFNα subtypes expressed by plasmacytoid dendritic cells (pDCs) following HIV-1 exposure ex vivo had relatively weak antiviral activity. These weakly antiviral IFNα subtypes include IFNα2, the only IFNα subtype approved for clinical use, and IFNα1, a potential antagonist of type I IFN signaling. To date, in-depth studies on the regulation and biological properties of the IFNα subtypes and IFNβ in primary pDCs and gut cells has not yet been undertaken. Paradoxically, the type I IFNs were also linked to chronic immune activation, a strong predictor of HIV-1 disease progression. The phenotype is likely due to the immunomodulatory properties of the type I IFNs, but the exact mechanisms remain unclear. Of note, gut barrier dysfunction occurs early in HIV-1 infection, leading to the translocation of microbes into the lamina propria, resulting in immune activation. We reported that gram-negative commensal bacteria enriched in the gut mucosa of HIV-1-infected individuals enhanced HIV-1 replication and CD4+ T cell death ex vivo in the gut Lamina Propria Aggregate Culture (LPAC) model. Here, we hypothesize that the transition from a protective to a pathogenic role for type I IFNs may be driven by translocating enteric microbes. Microbial exposure may raise the threshold for the antiviral effects of type I IFNs to manifest and `license' immunomodulatory ISGs to promote myeloid (mDC) activation/trans-infection and CD4+ T cell infection/ apoptosis. These microbe-driven pathogenic effects of type I IFNs may be sustained during chronic infection. Interestingly, we observed that type I IFN responses during chronic HIV-1 infection are compartmentalized in vivo, with differentially enhanced IFNα versus IFNβ in the blood versus the gut, respectively. To date, the cellular sources and mechanisms driving the elevated type I IFN signature in the gut remains unknown. We thus propose to investigate the role of type I IFNs in gut HIV-1 infection during the acute stage, at the onset of microbial translocation, and during the chronic stage. In Aim 1, we will evaluate the regulation, anti-HIV-1 activity and functional properties of the IFNα subtypes and IFNβ. In Aim 2, we will determine how type I IFNs modulate mDC activation and T cell function/survival in the context of HIV-1-associated gut dysbiosis and microbial translocation. In Aim 3, we will determine the source and triggers of abnormal type I IFN signature during chronic infection using gut tissues from uninfected, untreated HIV-1-infected and HIV-1-suppressed individuals. The results should provide urgently needed insights on how type I IFNs impact HIV-1 pathogenesis that may inform strategies to either harness these antiviral cytokines for curative strategies or block their immune effects to reduce chronic inflammation.