In the instruction book of life, which is the human genome, there are some mysterious particles that tend to remain silent, without making noise or any function, for thousands and thousands of years. They are a species of ancestral viruses, remnants of ancient pandemics, that were embedded in the DNA of germ cells (eggs or sperm), and were passed from generation to generation. Until today. 8% of the human genome is made up of these disturbing viral relics about which not much is still known. The little that has been discovered, for now, is that, when they are resurrected and activated, they can end up playing a key role in health or disease: for example, sequences of these very ancient viruses have been described that can help develop placenta or to encourage tumors and neurodegenerative diseases.
They are human endogenous retroviruses (HERV), viral relics without infective capacity that remained in the body after infections that our ancestors suffered millions of years ago. As with HIV, those very ancient retroviruses inserted themselves into the genetic material of the cells to replicate. In that case, at some point in evolution, these viruses infected germ cells and snuck viral genetic material into the genome of our species, perpetuating their presence for thousands and thousands of years. “It has been seen that some are common in other mammals, so they may have been from a time of pandemic. For it to have an impact on evolution, it had to be a huge pandemic, which affected many mammals and where they had the ability to access germ cells and expand,” explains María del Mar Tomás, microbiologist at the University Hospital Complex of A Coruña and spokesperson for the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC).
For a long time, these vestiges of past infections were considered silent passengers in our genome. Defective or turned off by epigenetic changes, they were even considered part of the so-called junk DNA because they did not code for proteins. However, the scientific community has been outlining their role within the body a little more and has discovered that they are present in healthy and diseased tissues, and in all of them they can have a function. “With evolution they have acquired multiple functions. Some of these particles have good functions, such as modulating immunity or protecting us from other viruses; but others are activated in a bad way and can cause illness. Before it was much more associated with the disease, but other researchers have found particles ancestral viral infections in healthy tissue, so in diseases, something else has to be activated. There may be external factors that cause them to be activated and can influence health and illness,” reflects Tomás.
There are still many questions in the air, such as what mechanism drives their activity or their silence. But science has already begun to relate its expression to signs of health or illness. “It is unclear whether the expression of endogenous retroviruses that accompanies neuroinflammation is beneficial or detrimental. Emerging evidence from studies now supports that HERV-K overexpression [un tipo de retrovirus endógeno humano] in the human brain it is not harmful and can exert neuroprotective effects,” explains a group of Chinese and Italian researchers in an article published in the magazine Frontiers in Microbiology. These endogenous retroviruses have also been shown to be involved in embryonic growth: syncytin, for example, is a protein originated by a gene derived from viruses embedded in the organism millions of years ago and has a key function in helping to form the membrane. of the placenta that attaches to the uterus.
A study published in Magazine Science pointed out that some of these pieces of viral DNA spread throughout the genome participate in the regulation of essential immune functions. Specifically, within the innate immune system, which is the first line of defense against germs. “The selfish genetic elements, like these endogenous retroviruses, can spread throughout the genome; “If one of the elements ends up near a gene involved in the immune system, natural selection can act to keep the element there, and then it becomes part of the innate immune response,” one of the authors of the study explained to this newspaper in 2016. study, geneticist Nels Elde. Tomás also highlights the role of these viral relics in the body’s defense: “They have the ability to activate interferons.” [proteínas que modulan la respuesta inmunitaria]”.
Involved in the development of tumors
Not all of them, however, are good features. He HERV-K It has multiple copies in the human genome and one of its subtypes, HML-2, is also associated with certain types of cancer and neurodegenerative diseases when it is aberrantly expressed in adult tissues. “HML-2 has been implicated in the development of cancer, since its expression has been associated with many types of tumors, such as teratocarcinoma, germ cell tumors, melanoma, ovarian and prostate cancer,” he lists. another study from the US National Institutes of Health.
In this line, an investigation Recent research has also associated the activity of this type of viral relics with the development of glioblastoma, one of the brain tumors with the worst prognosis. “We report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes,” the authors explained. Joan Seoane, ICREA research professor and co-director of the Preclinical and Translational Research Program of the Vall d’Hebron Institut d’Oncologia (VHIO), admits that knowledge about the role of these ancient virus fragments is still very limited: “We know very little , but we suspect that this is very important.”
The scientists’ hypothesis is that these integrated retrovirus remains acquire mutations and change without anything happening, but the organism does not like them and silences them with the epigenome, which is that entire network of chemical compounds and proteins that stick to the cells. genes and, although they do not modify their sequence, they do cause chemical variations that affect their functions. “So, in normal cells, with the epigenome controlled, nothing happens, but in tumors, where everything is deregulated and there is DNA hypomethylation [este fenómeno contribuye al origen de las células cancerosas al crear una inestabilidad cromosómica], the most recent viral remnants can wake up. Cancer, being aberrant, awakens things that we have silenced for millions of years,” explains Seoane.
“Cancer, being aberrant, awakens things that we have silenced for millions of years”
Joan Seoane, co-director of the Preclinical and Translational Research Program at the Vall d’Hebron Institut d’Oncologia (VHIO)
These viral relics have also been found to have a role in cellular aging. Research recently published in the magazine cell has observed – in monkey organs and in human tissues – that these pieces of ancient viruses (specifically, HML-2) can be reactivated and cause the formation of retrovirus-like particles within the cells responsible for aging and cancer. “It is clear that many of these sequences [de virus integradas en el ADN humano] “They begin to get out of control throughout our lives and are associated with most diseases: cancer, neurodegenerative, cartilage, muscle,” Spanish scientist Juan Carlos Izpisua, co-author of the study, told this newspaper a few months ago. According to the researchers, in experiments with cells in the laboratory they saw that these genetic fossils could reach other younger cells and cause them to age.
These same authors have also delved into another study on the degeneration of neurons during aging and have reported, in monkeys and humans, that the resurrection of endogenous retroviruses promote an immune response and “ultimately, the degeneration of neurons.” In in vivo and in vitro models, the study also demonstrates that silencing these viral relics inhibits neuronal senility associated with aging.
Regarding the role of HML-2 in health and disease, the scientific literature has also reported a relationship between these particles and amyotrophic lateral sclerosis (ALS): HERV-K RNA sequences have been detected in motor neurons of patients with ALS and it has been observed that an “increased expression of the HERV-K envelope protein in upper and lower motor neurons was neurotoxic and capable of causing cellular degeneration,” he points out. an italian studio. In the line of neurological diseases, the activation of several HERV families has also been associated with a greater risk of multiple sclerosis and a relationship has also been found between the activity of certain viral relics and the development of schizophrenia.
Pending unknowns
The field of study on HERVs is very broad and there are still many doubts to be resolved about their activation mechanisms, how they behave and, above all, how to tackle them if, as dozens of investigations suggest, they play an essential role in the development of some diseases. Regarding the influence of HERVs on glioblastoma, Seoane states: “We still need to know what mechanism gives a selective advantage to the tumor, how it helps the cancer grow.”
Overall, regarding the mechanisms that make these viral vestiges resurrect, Tomás also insists: “We have to see what these mechanisms are that cause some cells and humans to have them and others not. Maybe there are certain types of specific transposons [implicados]”. Transposons are DNA sequences capable of replicating and, like a kind of jumping genes, inserting themselves into other parts of the genome. Endogenous retroviruses are just one type of them, but there are more. The microbiologist advocates finding therapeutic targets in this field to block and eliminate them: “You cannot block all retroviruses because some may have good functions, but you could treat these transposons, even with CRISPR [una especie de tijera genética para editar el genoma] or with antibodies.”
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