在人类中,HIV-1感染诱导主要由I型干扰素(IFN)介导的先天免疫应答。I型IFN通过上调具有不同抗HIV特性的IFN刺激基因的表达来限制HIV-1的复制。在这项研究中,我们报道,细胞膜蛋白奥托铁蛋白(OTOF)作为I型IFN诱导的效应,抑制HIV-1进入髓系巨噬细胞和树突状细胞(DC)。OTOF在巨噬细胞和DC中被I型IFN显著诱导,但在CD4+T淋巴细胞中不被诱导。沉默OTOF消除了IFN介导的对巨噬细胞和DC中HIV-1感染的抑制。此外,OTOF过表达在巨噬细胞和CD4+T细胞中表现出抗HIV活性。进一步的证据表明OTOF抑制HIV-1在细胞膜处进入靶细胞。总的来说,OTOF是I型IFN诱导的抑制HIV-1进入巨噬细胞的下游分子;它是治疗HIV感染的新的潜在药物。重要性在HIV-1感染患者中,病毒被引发I型干扰素(IFN)产生的先天性免疫传感器识别,它们是众所周知的细胞因子,通过诱导抗病毒基因的表达发挥广泛的抗病毒作用。通过比较未经治疗的患者和健康供体的基因表达谱,我们系统地鉴定了OTOF是IFN-α在原代巨噬细胞和树突状细胞(DC)中诱导的一种新的抗病毒基因。此外,沉默OTOF可减轻IFN-α诱导的骨髓细胞谱系巨噬细胞和DC对HIV-1感染的抗性。相比之下,OTOF过表达有效地限制了巨噬细胞中的HIV-1传播。我们进一步探索了OTOF通过其抑制跨细胞膜的HIV-1病毒体的分子机制。总的来说,OTOF是一种新发现的I型IFN诱导的抗病毒因子,可抑制骨髓细胞中HIV-1的跨膜活性。
In humans, HIV-1 infection induces innate immune responses mediated mainly by type I interferon (IFN). Type I IFN restricts HIV-1 replication by upregulating the expression of IFN-stimulated genes with diverse anti-HIV properties. In this study, we report that the cell membrane protein otoferlin (OTOF) acts as a type I IFN-induced effector, inhibiting HIV-1 entry in myeloid lineage macrophages and dendritic cells (DCs).
OTOF is significantly induced by type I IFN in macrophages and DCs but not in CD4+ T lymphocytes. Silencing
OTOF abrogates the IFN-mediated suppression of HIV-1 infection in macrophages and DCs. Moreover,
OTOF overexpression exhibits anti-HIV activity in macrophages and CD4+ T cells. Further evidence reveals that
OTOF inhibits HIV-1 entry into target cells at the cell membrane. Collectively, OTOF is a downstream molecule induced by type I IFN to inhibit HIV-1 entry in macrophages; it is a new potential agent for the treatment of HIV infection. IMPORTANCE In patients with HIV-1 infection, the virus is recognized by innate immune sensors that trigger the production of type I interferons (IFNs), which are well-known cytokines that exert broad antiviral effects by inducing the expression of antiviral genes. By comparing the gene expression profiles of untreated patients and healthy donors, we systematically identified OTOF as a new antiviral gene induced by IFN-α in primary macrophages and dendritic cells (DCs). Additionally, silencing OTOF alleviates IFN-α-induced resistance to HIV-1 infection in both myeloid cell lineage macrophages and DCs. In contrast,
OTOF overexpression potently restricts HIV-1 transmission in macrophages. We further explored the molecular mechanism through which OTOF inhibits the HIV-1 virion across the cell membrane. Overall, OTOF is a newly identified type I IFN-induced antiviral factor that inhibits the transmembrane activity of HIV-1 in myeloid cells.