By Katie Lau
In July 2017, the French biologist Odile Heidmann and researchers at the Gustave Roussy Cancer Institute discovered a viral protein that streams through the veins of pregnant women. Hemo is produced by the fetus and originates from an ancient virus that once infected our ancestors. The retroviral envelope gene is highly expressed in germ cell, breast, and ovarian tumours, as well as stem cells and induced pluripotent stem cells (Heidmann et al., 2017).
Hemo is not the only example of a viral gene inhabiting our DNA. The effect this viral DNA has on us is not fully understood yet. Such ancient viruses, like hemo, however, either protect or harm our health. Most viral DNA originates from a specific type: retroviruses. These insert their RNA genome into our DNA genome once they have infected cells. The cell’s gene expression machinery is used to transcribe and translate these viral genes – producing more budding viral proteins that infect nearby cells. If a retrovirus infects egg or sperm cells, the virally infected DNA can be passed down successive generations. Eventually, these inherited stowaways are known as endogenous retroviruses (ERVs) (Zimmer, 2017). Roughly 5-8% of the human genome is composed of ERVs – around 98,000 elements and fragments (Belshaw et al., 2004). ERVs will initially exploit the cell to replicate themselves, thereby infecting as many cells as possible. However, over generations, the viral DNA mutates – coding for non-functional viral proteins and halting infection (Zimmer, 2017).
Similar to defences against other viruses, humans have also developed ERV defences. TIP60 is an enzyme that represses activation of endogenous retroviral elements through regulating histone methylation. It is known to be a tumour suppressor, and its downregulation has been associated with tumorigenesis (Rajagopalan et al., 2018). Therefore, these viral genes are switched on occasionally. Some ERVs produce proteins in certain types of tumour cells, leading to the question: can endogenous retroviruses increase the risk of cancer? (Zimmer, 2017).
Researchers have found a common strategy used to combat viruses, a method which has also contributed to human evolution: loading them with mutations. They achieve this with a family of enzymes called apolipoprotein B mRNA editing catalytic polypeptide-like, or APOBECs. When the DNA is unwound, during repair, replication or transcription, these enzymes scan for any viral DNA, removing bases and replacing them with others. However, this mechanism can also target non-viral regions of the genome, introducing mutations that could lead to disease. These mutations would have been removed from the population due to the affected organism being unable to survive and reproduce. But recently, these APOBECs have been associated with cancers (Pinto et al., 2016). On the other hand, demonstrating the complicated relationship humans have with ERVs, there is evidence for ERVs conferring protection against cancer rather than inducing it. ERV9 detects cancer-related damage in the DNA of male germline cells. It’s a long terminal repeat (LTR) that acts as a promoter to initiate expression of the male germ cell-associated transcriptionally active p63 gene (GTAp63), which activates apoptosis, ensuring these cancerous cells do not continue dividing (Beyer et al., 2016).
Scientists have also found the remarkable role that ERVs play in our early fetal development. The ERV-derived gene syncytin originally encoded viral envelope proteins, enabling retroviruses to fuse with the host cell membrane and successfully infect. However, the human body has exploited this mechanism for its own purposes: developing the placenta during pregnancy. Syncytin’s cell fusing mechanism is now used to facilitate formation of the cell layer that joins the placenta with the uterus. This retroviral integration into the primate germ line is estimated to have occurred more than 25 million years ago (Voisset et al., 1999).
The early embryo has proven itself to be a hotbed of ERV activity – further shown by hemo. Dr Heidmann and her colleagues found that the gene encoding this protein is present in many primates, and more surprisingly, has barely changed between species – demonstrating its importance: “It simply isn’t a relic”, says Heidmann. Any mutations in this gene would have been fatal to the affected organism. The placenta produces hemo, as do other cells in embryonic development, but the reasons why remain unknown. Heidmann believes it is possible hemo acts a messenger from the fetus to the mother, signalling to her immune system not to attack it (Zimmer 2017).
In other words, we are still uncovering the incredible antiviral mechanisms and physiological functions that humans and other primates have acquired from our enemies themselves. Whether these endogenous retroviruses can be our future friends or foes, defenders or inducers of disease – the answer is not clear cut. However, building up this body of knowledge will always allow for more targeted, innovative diagnosis and treatment of the current incurable illnesses faced.
Belshaw, R., Pereira, V., Katzourakis, A., Talbot, G., Pačes, J., Burt, A. & Tristem, M. (2004) Long-term reinfection of the human genome by endogenous retroviruses. Proceedings of the National Academy of Sciences of the United States of America. 101 (14), 4894-4899. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC387345/. [Accessed 12th November 2020].
Beyer, U., Krönung, S. K., Leha, A., Walter, L. & Dobbelstein, M. (2016) Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death. Cell Death and Differentiation. 23 (1), 64-75. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26024393. [Accessed 12th November 2020]
Heidmann, O., Béguin, A., Paternina, J., Berthier, R., Deloger, M., Bawa, O. & Heidmann, T. (2017) HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors. Proceedings of the National Academy of Sciences of the United States of America. 114 (32), E6642-E6651. Available from: doi: 10.1073/pnas.1702204114.
Pinto, Y., Gabay, O., Arbiza, L., Sams, A. J., Keinan, A. & Levanon, E. Y. (2016) Clustered mutations in hominid genome evolution are consistent with APOBEC3G enzymatic activity. Genome Research. 26 (5), 579-587. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27056836. [Accessed 12th November 2020]
Rajagopalan, D., Tirado-Magallanes, R., Bhatia, S. S., Teo, W. S., Sian, S., Hora, S., Lee, K. K., Zhang, Y., Jadhav, S. P., Wu, Y., Gan, Y., Karnani, N., Benoukraf, T. & Jha, S. (2018) TIP60 represses activation of endogenous retroviral elements. Nucleic Acids Research. 46 (18), 9456-9470. Available from: doi: 10.1093/nar/gky659.
Voisset, C., Blancher, A., Perron, H., Mandrand, B., Mallet, F. & Paranhos-Baccala, G. (1999) Phylogeny of a Novel Family of Human Endogenous Retrovirus Sequences, HERV-W, in Humans and Other Primates. AIDS Research and Human Retroviruses. 15 (17), 1529-1533. Available from: https://www.liebertpub.com/doi/10.1089/088922299309810. [Accessed 14th November 2020].
Zimmer, C., 2017. Ancient Viruses Are Buried In Your DNA. Available from: <https://www.nytimes.com/2017/10/04/science/ancient-viruses-dna-genome.html#:~:text=Most%20of%20our%20viral%20DNA,genes%20into%20that%20cell’s%20DNA.> [Accessed 12th November 2020].