Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Virol. 2014 Jun;88(12):6993-7004. doi: 10.1128/JVI.00638-14. Epub 2014 Apr 9.
Gammaherpesviruses are ubiquitous pathogens that establish a lifelong infection and are associated with cancer. In spite of the high seroprevalence of infection, the risk factors that predispose the host toward gammaherpesvirus-induced malignancies are still poorly understood. Interferon (IFN) regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. On the basis of its biology, IRF-1 represents a plausible host factor to attenuate gammaherpesvirus infection and tumorigenesis. In this study, we show that IRF-1 restricts gammaherpesvirus replication in primary macrophages, a physiologically relevant immune cell type. In spite of the known role of IRF-1 in stimulating type I IFN expression, induction of a global type I IFN response was similar in IRF-1-deficient and -proficient macrophages during gammaherpesvirus infection. However, IRF-1 was required for optimal expression of cholesterol-25-hydroxylase, a host enzyme that restricted gammaherpesvirus replication in primary macrophages and contributed to the antiviral effects of IRF-1. In summary, the current study provides an insight into the mechanism by which IRF-1 attenuates gammaherpesvirus replication in primary immune cells, a mechanism that is likely to contribute to the antiviral effects of IRF-1 in other virus systems.
Interferon regulatory factor 1 (IRF-1) is a transcription factor that regulates innate and adaptive immune responses and functions as a tumor suppressor. IRF-1 restricts the replication of diverse viruses; however, the mechanisms responsible for the antiviral effects of IRF-1 are still poorly understood. Gammaherpesviruses are ubiquitous pathogens that are associated with the induction of several malignancies. Here we show that IRF-1 expression attenuates gammaherpesvirus replication in primary macrophages, in part by increasing expression of cholesterol-25-hydroxylase (CH25H). CH25H and its product, 25-hydroxycholesterol, restrict replication of diverse virus families. Thus, our findings offer an insight into the mechanism by which IRF-1 attenuates the replication of gammaherpesviruses, a mechanism that is likely to be applicable to other virus systems.
γ疱疹病毒是普遍存在的病原体，可导致终生感染，并与癌症有关。尽管感染的血清阳性率很高，但导致宿主易患γ疱疹病毒诱导的恶性肿瘤的危险因素仍知之甚少。干扰素（IFN）调节因子 1（IRF-1）是一种肿瘤抑制因子，也参与固有和适应性免疫反应的调节。基于其生物学特性，IRF-1 代表了一种减弱 γ疱疹病毒感染和肿瘤发生的合理宿主因子。在这项研究中，我们表明 IRF-1 限制了原发性巨噬细胞中的 γ疱疹病毒复制，这是一种具有生理相关性的免疫细胞类型。尽管已知 IRF-1 在刺激 I 型 IFN 表达中的作用，但在 γ疱疹病毒感染期间，IRF-1 缺陷型和野生型巨噬细胞中的 I 型 IFN 反应诱导相似。然而，IRF-1 是最佳表达胆固醇-25-羟化酶所必需的，胆固醇-25-羟化酶是一种宿主酶，可限制原发性巨噬细胞中的 γ疱疹病毒复制，并有助于 IRF-1 的抗病毒作用。总之，本研究深入了解了 IRF-1 减弱原发性免疫细胞中 γ疱疹病毒复制的机制，这一机制可能有助于解释 IRF-1 在其他病毒系统中的抗病毒作用。
干扰素调节因子 1（IRF-1）是一种转录因子，可调节固有和适应性免疫反应，并作为肿瘤抑制因子发挥作用。IRF-1 限制多种病毒的复制；然而，IRF-1 的抗病毒作用的机制仍知之甚少。γ疱疹病毒是普遍存在的病原体，与多种恶性肿瘤的诱导有关。在这里，我们表明 IRF-1 的表达减弱了原发性巨噬细胞中 γ疱疹病毒的复制，部分是通过增加胆固醇-25-羟化酶（CH25H）的表达。CH25H 和它的产物 25-羟胆固醇限制了多种病毒家族的复制。因此，我们的发现提供了一个深入了解 IRF-1 减弱 γ疱疹病毒复制的机制的视角，这一机制可能适用于其他病毒系统。
