Abstract：
Interferon (IFN) -stimulated genes (ISGs) are critical effectors of IFN response to viral infection, but whether ISG expression is a correlate of protection against HIV infection remains elusive. A well-characterized subcohort of Kenyan female sex workers, who, despite being repeatedly exposed to HIV-1 remain seronegative (HESN), exhibit reduced baseline systemic and mucosal immune activation. This study tested the hypothesis that regulation of ISGs in the cells of HESN potentiates a robust antiviral response against HIV. Transcriptional profile of a panel of ISGs with antiviral function in PBMC and isolated CD4+ T cells from HESN and non-HESN sex worker controls were defined following exogenous IFN-stimulation using relative RT-qPCR. This study identified a unique profile of proinflammatory and proapoptotic ISGs with robust but transient responses to exogenous IFN-γ and IFN-α2 in HESN cells. In contrast, the non-HESN cells had a strong and prolonged proinflammatory ISG profile at baseline and following IFN challenge. Potential mechanisms may include augmented bystander apoptosis due to increased TRAIL expression (16-fold), in non-HESN cells. The study also identified two negative regulators of ISG induction associated with the HESN phenotype. Robust upregulation of SOCS-1 and IRF-1, in addition to HDM2, could contribute to the strict regulation of proinflammatory and proapoptotic ISGs in HESN cells. As reducing IRF-1 in the non-HESN cells resulted in the identified HESN ISG profile, and decreased HIV susceptibility, the unique HESN ISG profile could be a correlate of protection against HIV infection.
摘要：
干扰素（IFN）刺激基因（ISGs）是IFN对病毒感染反应的关键效应，但是ISG的表达是否与HIV感染的保护作用相关仍然难以捉摸。肯尼亚女性性工作者的特征亚组，谁,尽管反复暴露于HIV-1仍然是血清阴性（HESN），表现出降低的基线全身和粘膜免疫激活。这项研究检验了以下假设：HESN细胞中ISG的调节增强了针对HIV的强大抗病毒反应。在使用相对RT-qPCR的外源性IFN刺激后，定义PBMC中具有抗病毒功能的一组ISG的转录谱和来自HESN和非HESN性工作者对照的分离的CD4T细胞。这项研究确定了促炎和促凋亡ISGs的独特特征，对HESN细胞中的外源性IFN-γ和IFN-α2具有强烈但短暂的反应。相比之下,在基线时和IFN攻击后,非HESN细胞的促炎性ISG谱表现强烈且延长.潜在的机制可能包括由于TRAIL表达增加（16倍）而导致的旁观者凋亡增加，在非HESN细胞中。该研究还鉴定了与HESN表型相关的ISG诱导的两个负调节因子。除HDM2外，SOCS-1和IRF-1的强烈上调可能有助于严格调节HESN细胞中的促炎和促凋亡ISGs。由于在非HESN细胞中减少IRF-1导致鉴定的HESNISG谱,和降低艾滋病毒易感性，独特的HENSISG谱可能与抗HIV感染的保护相关.
