Immunity & Ageing ( IF 7.9 ) Pub Date : 2021-03-26 , DOI: 10.1186/s12979-021-00228-x Mikko Hurme , Graham Pawelec
Over evolutionary time, the human genome has incorporated large amounts of genetic material from ancient retroviral infections, comprising ca. 8% of the total DNA. The majority of human endogenous retroviruses (HERVs) are defective due to the accumulation of mutations and deletions but some proviruses, especially in the youngest families (e.g. HERV-K (HML-2), contain intact genes permitting the production of proviral proteins (for a review, see [1]). The functions of HERVs have been under active investigation for decades and it is now known that far from being quiescent, some are involved in several crucial physiologic processes, clearly advantageous or essential to the host, e.g. placentation, neuroprotection and differentiation of cells in early embryos. However, there are now many publications also showing that HERVs are involved in the pathogenesis of several diseases (autoimmune, inflammatory, malignancies) [1].
The regulation of the expression of HERVs is very complex. In healthy individuals their activation is controlled by epigenetic mechanisms, but some constitutive expression is observed in several organs of the body. It is obvious that genetic location of the provirus is decisive in the regulation of its expression, i.e. provirus insertions can be within or nearby a gene, resulting in a complex network of inductive signals. Therefore, studies demonstrating associations between HERV expression and a given disease condition would be more informative if the location of the provirus, and its surroundings, would be analyzed. One obvious pathogenetic mechanism would naturally be the production of new infective viruses, which would then insert into the genome as a provirus and modify the expression of the surrounding genes (insertional mutagenesis). Thus far, however, there is no evidence that this mechanism would be functional in humans. In addition to these complexities in the regulation of the transcription of HERVs, it is now known that the end products, i.e. the env, gag, pol-encoded proteins, are directly involved in the pathogenesis of some diseases, especially those of an autoimmune nature [2]. It seems that these proteins (especially env) can be recognized as foreign and are able to induce the production of autoantibodies (the shared epitope model). Also in this case it is probable that the various proviruses would have a different effect (i.e. the protein should be intact enough to be able to activate antibody production, but should also express the shared epitope).
There is now evidence that the aging-associated changes in the defense mechanisms of the body modify the response against HERVs (eg. immunosenescence). For example, the activity of the HERV-K (HML-2) provirus at 1q22, which is relatively intact, is increased in older adults, and its expression is associated with a neutrophil-dominated inflammatory response [3]. As transcriptional changes in this response were very similar to those observed in influenza infection, in this respect it seems that this HERV behaves like a normal virus. Now, in a pre-print (not yet peer-reviewed) [4], Liu et al. have addressed the issue of the role of HERVs in cellular senescence, which is of major importance in ageing and inflammageing. Using various in vitro senescence models with cells from healthy individuals or from progeroid syndrome patients they observed high expression of several retroelements, including the HERV-K (HML-2) family retroviruses. This expression was probably due to the loss of epigenetic control (i.e. the same mechanism regulating the expression of HERVs in early embryonic cells). This expression also led to the production of HERV-K (HML-2) env protein. To examine the possible functions of the HERVs produced in the culture supernatants of senescent cells, they added this to cultures of “younger” cells and, surprisingly, a more rapid induction of senescence was observed. Moreover, treatment of the culture supernatant with anti-Env antibodies abolished this senescence-enhancing effect. Thus, they concluded that the HERV-Env protein is a major player in senescence induction in these in vitro models. Should it transpire that is also has a role in vivo in cell types the ageing of which resembles that observed in the in vitro senescence models, a new avenue for understanding and manipulating ageing processes in humans may be opened up.
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Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Mikko Hurme
Department of Immunology, University of Tübingen, Tübingen, Germany
Graham Pawelec
Health Sciences North Research Institute, Sudbury, Ontario, Canada
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Hurme, M., Pawelec, G. Human endogenous retroviruses and ageing. Immun Ageing 18, 14 (2021). https://doi.org/10.1186/s12979-021-00228-x
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DOI: https://doi.org/10.1186/s12979-021-00228-x
中文翻译：
人内源性逆转录病毒和衰老
在进化过程中，人类基因组已整合了来自古代逆转录病毒感染的大量遗传物质，其中包括约 占总DNA的8％。大多数人类内源性逆转录病毒（HERV）由于突变和缺失的积累而存在缺陷，但是某些原病毒，特别是在最年轻的家族中（例如HERV-K（HML-2）），含有完整的基因，可以生产原病毒蛋白（例如综述，请参见[1]。HERV的功能已经进行了数十年的积极研究，现在知道，HERV不仅处于静止状态，而且还参与了几个关键的生理过程，这些过程对于宿主而言显然是有利的或必不可少的，例如胎盘植入，早期胚胎中细胞的神经保护和分化。
HERV表达的调节非常复杂。在健康个体中，它们的激活受表观遗传机制控制，但是在身体的几个器官中观察到一些组成型表达。显然，前病毒的遗传位置在其表达的调节中起决定性作用，即前病毒插入可能位于基因内或基因附近，从而导致复杂的诱导信号网络。因此，如果能够分析原病毒的位置及其周围环境，那么证明HERV表达与给定疾病状况之间相关性的研究将提供更多信息。一种明显的致病机制自然是产生新的传染性病毒，然后将其作为原病毒插入基因组并修饰周围基因的表达（插入诱变）。然而，到目前为止，尚无证据表明该机制可在人类中发挥作用。除了在HERV转录调控中的这些复杂性外，现在还知道最终产物，即env，gag，pol编码蛋白直接参与某些疾病的发病机理，尤其是自身免疫性质的疾病[2]。似乎这些蛋白质（尤其是env）可以被识别为外源蛋白质，并且能够诱导自身抗体的产生（共享表位模型）。同样在这种情况下，各种原病毒可能也会产生不同的作用（即蛋白质应完整无损，以能够激活抗体的产生，但也应表达共享的表位）。
现在有证据表明，机体防御机制中与衰老相关的变化会改变对HERV的反应（例如免疫衰老）。例如，在老年人中，相对完整的HERV-K（HML-2）原病毒的活性在老年人中增加了，并且其表达与中性粒细胞为主的炎症反应有关[3]。由于这种反应的转录变化与流感感染中观察到的非常相似，因此从这个方面看，这种HERV的行为就像正常病毒一样。现在，Liu等人在预印本（尚未经过同行评审）中[4]。已经解决了HERV在细胞衰老中的作用的问题，这在衰老和发炎中至关重要。使用来自健康个体或早老症患者的细胞的各种体外衰老模型，他们观察到了几种逆转录因子的高表达，包括HERV-K（HML-2）家族逆转录病毒。该表达可能是由于失去了表观遗传控制（即，调节早期胚胎细胞中HERV表达的相同机制）。这种表达还导致了HERV-K（HML-2）env蛋白的产生。为了检查在衰老细胞的培养上清液中产生的HERV的可能功能，他们将其添加到“年轻”细胞的培养物中，令人惊讶的是，观察到了更快的衰老诱导。而且，用抗Env抗体处理培养物上清液消除了这种衰老增强作用。因此，他们得出结论，在这些体外模型中，HERV-Env蛋白是衰老诱导的主要参与者。如果它在细胞类型中也具有体内作用，其衰老类似于在体外衰老模型中观察到的细胞类型，则可能会为理解和操纵人类衰老过程开辟一条新途径。
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Autio A，Nevalainen T，Mishra BH，JylhäM，Flinck H，Hurme M.衰老对与1q22 HERV-K（HML-2）前病毒表达相关的转录组学变化的影响。免疫老化。2020; 17（1）：11。https://doi.org/10.1186/s12979-020-00182-0。
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坦佩雷大学医学与卫生技术学院，坦佩雷，芬兰
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蒂宾根大学免疫学系，德国蒂宾根
格雷厄姆·帕维尔克
加拿大安大略省萨德伯里市卫生科学研究所北部研究所
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Hurme，M.，Pawelec，G.人类内源性逆转录病毒和衰老。与免疫老化 18， 14（2021）。https://doi.org/10.1186/s12979-021-00228-x
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