Table_1_Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses.DOCX

About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

人类基因组中约有8%的序列源自病毒，即人类内源性逆转录病毒（human Endogenous Retroviruses, HERVs）。HERVs是远古感染遗留的遗迹：在过去1亿年间，此类病毒曾感染灵长类生殖细胞谱系，并以稳定元件的形式扎根于宿主自身DNA与外源DNA的交界区域。值得关注的是，HERVs与宿主的共演化过程催生了对原本服务于逆转录病毒生命周期的功能的驯化，为宿主细胞赋予了全新的生物学功能。例如，经过筛选的HERVs包膜蛋白已被招募用于妊娠相关生理过程，而前病毒长末端重复序列（Long Terminal Repeats）则参与调控多种细胞基因的转录。鉴于HERVs稳定整合于宿主基因组，且在绝大多数健康组织中呈现基础表达水平，人体免疫防御系统理应抑制HERV介导的免疫激活。尽管如此，HERVs及其产物（包括RNA、胞质DNA与蛋白质）仍能够调控宿主免疫系统，并受其影响，这一现象引人入胜地暗示了其在人类先天免疫的演化与功能发挥中具有核心作用。事实上，HERV序列是塑造并拓展干扰素信号网络的核心参与者：其所携带的可诱导基因曾在多种哺乳动物类群中被驯化并弥散分布。此外，HERV整合至编码关键免疫因子的基因内部或其邻近区域的现象，已被证实会影响这些基因的活性，或是导致其在人群中出现多态性变异——例如主要组织相容性复合体（major histocompatibility complex, MHC）区域内的HERV-K(HML10)前病毒。除此之外，研究证实HERV的表达产物可调控先天免疫效应因子，因此此类产物一方面与炎症性疾病及自身免疫紊乱紧密相关，另一方面又可通过自身的免疫抑制特性，对过度的免疫激活起到负调控作用。最后，有研究提出HERVs可对宿主抵御外源感染起到保护作用。本综述总结了HERVs及其产物在先天免疫应答中的参与情况，阐述了它们与人体第一道免疫防线之间的复杂互作如何既能主动为宿主提供保护，也可能造成宿主损伤，这意味着HERV表达的留存与基础免疫警戒的维持之间存在微妙的平衡。