Quotation: Srinivasachar Badarinarayan S, Sauter D (2022) Not all viruses trigger illness: HERV-Ok(HML-2) in wholesome human tissues. PLoS Biol 20(10):
e3001884.
https://doi.org/10.1371/journal.pbio.3001884
Revealed: October 31, 2022
Copyright: © 2022 Srinivasachar Badarinarayan, Sauter. That is an open entry article distributed underneath the phrases of the Inventive Commons Attribution License, which allows unrestricted use, distribution, and replica in any medium, supplied the unique creator and supply are credited.
Funding: DS is supported by funds of the German Analysis Basis (https://www.dfg.de/en/; Heisenberg Program: SA 2676/3-1, SFB1506, SA 2676/1-2), the Canon Basis Europe (https://www.canonfoundation.org/), and the German Middle for An infection Analysis (https://www.dzif.de/en). SSB is supported by the Nationwide Institutes of Well being (https://www.nih.gov/; UM1 AI164559; HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory). The funders had no function in examine design, knowledge assortment and evaluation, determination to publish, or preparation of the manuscript.
Competing pursuits: The authors have declared that no competing pursuits exist.
Viruses are in all places. They infect nearly all organisms on this planet. They are often discovered within the air we breathe, the flowers in our backyard, and the depths of the ocean. A few of them may even be present in our DNA. These so-called human endogenous retroviruses (HERVs) signify remnants of once-infectious viruses that turned mounted in our genome. Whereas a few of them nonetheless have the potential to provide virus-like particles, HERVs have misplaced their capability to generate infectious virions which are transmitted horizontally. As an alternative, they persist in our DNA as viral fossils which are handed on vertically from technology to technology.
Viruses are typically perceived as nasty pathogens, whose transmission and unfold should be prevented. Even the infectious ancestors of endogenous retroviruses could have been pathogenic, and expression of HERVs comparable to HERV-Ok(HML-2) has been related to most cancers, neurological problems, and different illnesses. Nevertheless, a number of HERVs have additionally been co-opted throughout evolution and exert essential physiological features. The prime examples are 2 virus-derived glycoproteins (Syncytin-1 and Syncytin-2) that mediate cell–cell fusion throughout placenta growth [1]. With out these viral proteins, regular being pregnant wouldn’t be attainable. Different HERVs regulate mobile gene expression. For instance, alcohol digestion is modulated by a virus-derived cis-regulatory ingredient enhancing expression of the alcohol dehydrogenase 1C gene (ADH1C) [2]. Some HERVs even contribute to antiviral immune responses, e.g., by regulating antiviral gene expression [3,4].
To raised perceive the function of HERVs in human well being and illness, a scientific comparability of their exercise in wholesome versus diseased tissues is required. Most earlier research, nonetheless, have focussed on HERV activation within the context of illness, and there may be restricted data on HERV expression in non-diseased tissues, notably on the degree of particular person HERV loci. On this subject, Burn and colleagues closed this hole by systematically analysing HERV transcription in additional than 50 wholesome tissues from nearly 1,000 donors [5] (Fig 1). The authors took benefit of RNA-sequencing datasets obtainable through the Genotype Tissue and Expression (GTEx) Challenge [6]. For his or her analyses, Burn and colleagues targeted on HERV-Ok(HML2). This ERV subclade represents the youngest HERV group and contains proviruses which are distinctive to people. Some HERV-Ok(HML-2) proviruses are even polymorphic within the human inhabitants and will contribute to inter-individual variation [7]. Like all HERVs, HERV-Ok(HML-2) insertions have collected quite a few deletions and mutations. Nonetheless, some HERV-Ok(HML-2) parts have retained intact open studying frames (ORFs) that will encode for practical proteins.
Fig 1. Endogenous retroviruses of the HERV-Ok(HML-2) subclade are broadly expressed in wholesome human tissues.
About 8% of the human genome include HERVs. By analysing the transcriptomes of greater than 13,000 human samples, Burn and colleagues present that HERV-Ok(HML-2), the evolutionarily youngest ERV subclade in people, is broadly expressed in wholesome cells and tissues. Significantly excessive HERV-Ok(HML-2) transcript ranges had been noticed within the cerebellum, pituitary, thyroid, and reproductive tissues. 5 HERV-Ok(HML-2) proviruses (situated at 1q21.3, 1q22, 3q12.3, 12q24.33, and 19q13.12b) had been expressed in nearly each tissue. The authors didn’t observe any affiliation of HERV-Ok(HML-2) expression with age and solely a minor affiliation with intercourse in some tissues (e.g., breast). Nevertheless, evolutionarily older HERV-Ok(HML-2) proviruses are typically expressed to larger ranges than their youthful counterparts. Intriguingly, a number of the expressed HERV-Ok(HML-2) repeats harbour intact open studying frames that will encode for Gag, Professional, Pol, Env, or Rec proteins in a number of wholesome tissues.
Intriguingly, HERV-Ok(HML-2) expression was detectable in all tissues examined. Significantly, excessive expression ranges had been noticed within the mind (cerebellum and pituitary), thyroid, and reproductive tissues (testes and ovaries) (Fig 1). The excessive ranges of HERV-Ok(HML-2) transcripts in reproductive tissues could also be a consequence of their ancestor’s capability to contaminate germ cells. To ascertain themselves within the human genome, retroviruses should enter the germ line. Thus, HERV-Ok(HML-2) has advanced from an exogenous retrovirus that contaminated germ cells and most certainly exploited mobile transcription elements which are extremely lively in reproductive tissues. These properties could permit environment friendly LTR-mediated HERV-Ok(HML-2) transcription in testes and ovaries right this moment. It’s tempting to take a position that expression of HERV-Ok(HML-2) in different tissues can also be a relic of the tissue tropism of the ancestral exogenous retrovirus. Alternatively, choice processes could have modified the expression patterns of HERV-Ok(HML-2) after their fixation within the host genome.
Importantly, Burn and colleagues didn’t solely analyse complete HERV-Ok(HML-2) transcription, but additionally expression of particular person HERV-Ok(HML-2) loci. They detected 37 HERV-Ok(HML-2) proviruses which are expressed in no less than 1 tissue. 5 of them (1q21.3, 1q22, 3q12.3, 12q24.33, and 19q13.12b) had been broadly transcribed in nearly each tissue (Fig 1).
Intriguingly, a number of the HERV-Ok(HML-2) loci expressed in wholesome tissues additionally comprise intact ORFs (Fig 1). For instance, gag-derived proteins could also be produced by the broadly expressed HERV-Ok(HML-2) locus 3q12.3 and/or 12q14.1, which is particularly expressed in kidneys. Though stability and potential features of those Gag proteins stay to be decided, HERV-derived Gag proteins could negatively intrude with the meeting of exogenous retroviruses [8]. Along with Gag, a practical Env protein expressed from HERV-Ok(HML-2) 7p22.1a could also be current in a number of wholesome tissues, together with blood. This specific Env protein has beforehand been proven to retain its fusogenic exercise [9] and will thus induce syncytia formation in several tissues, supplied that its receptor can be current. Notably, HERV-Ok(HML-2) 7p22.1a Env was additionally instructed to cut back HIV-1 an infection [10]. In addition to gag and env genes, intact HERV-Ok(HML-2) rec ORFs had been additionally proven to be expressed in varied tissues, confirming and increasing findings of an earlier examine [11]. HERV-Ok(HML-2) Rec might be thought-about a practical homolog of HIV Rev. Each proteins work together with RNA constructions and mediate the export of unspliced or incompletely spliced (viral) mRNA from the nucleus to the cytoplasm. Whereas the presence of rec transcripts in a number of wholesome tissues means that Rec proteins could have been co-opted by the human organism, the precise operate of Rec proteins in human cells stays to be decided.
In abstract, the transcriptome analyses by Burn and colleagues assist to determine lively HERV loci which are neither trigger nor consequence of illness, however could have impartial and even useful results. Their examine gives a useful dataset of wholesome controls that can be utilized to raised assess the relevance of HERV activation in aberrant cells. Notably, the identification of HERV-Ok(HML-2) ORFs strongly means that virus-derived proteins are regular parts of the human proteome in lots of tissues. Along with proteomic analyses, the findings by Burn and colleagues will subsequently additionally assist to evaluate the suitability of HERV proteins as biomarkers and their specificity for sure most cancers entities and different aberrant cells.
It needs to be borne in thoughts that the HERV-Ok(HML-2) group analysed within the current examine is just one of many HERV subclades. It stays to be decided whether or not different HERV members exhibit equally broad expression in wholesome cells and tissues. Furthermore, HERVs may also be lively with out being transcribed, e.g., by appearing as enhancers or suppressors of gene expression. Thus, the variety of HERVs which are lively in our cells is most certainly larger than we predict, and plenty of physiological HERV features stay to be found.
