by Joseph Timpona

We often think of viruses as foreign invaders– microscopic agents intent on making us sick before spreading to the next victim.  However, some viruses become enduring guests by hitchhiking a permanent ride in our genomes. In fact, scientists think that these special types of viruses, known as retroviruses, may have inadvertently allowed for the development of placental mammals including humans.

Retroviruses

Retroviruses contain their hereditary information in the form of RNA rather than the DNA that makes up our human genomes. However, once a retrovirus infects a cell, the RNA must be converted to DNA and inserted into the genome of the infected cell in order for the virus to make copies and spread.  Usually this integration can occur with no consequence – after all, a human being consists of trillions of cells. What’s the problem with a small subset containing a viral genome or two?

Well, when a retrovirus inserts its genome into a germ line cell (the cells responsible for generating egg and sperm), the viral DNA can be passed onto any offspring that arise from the egg or sperm containing the retroviral insertion. That offspring then carries the viral genome in every one of its cells.  Scientists now call this an endogenous, or native, virus.  After the repetition of this process many times throughout evolutionary history, about 8% of the human genome derives from retroviruses.  This is a huge portion of our genome, more than five times the DNA portion encoding human proteins.  We know this because viruses have very defined genomic patterns.  By scanning the bases comprising the human genome, similar to the way you search for a word in a page of text, scientists can look for viral hallmarks.  In total, our genome has thousands of endogenous retroviruses.

This may sound scary – our genomes being infested with viral remnants.  But, we are not walking virus incubators because the regions of DNA that comprise the viruses don’t typically produce any proteins. There are rare cases, however, in which humans and other mammals have hijacked viral genes to provide a beneficial function. The most common viral gene captured in this sense is the gene encoding the fusion protein.

Viral fusion proteins

Retroviruses, as well as many other viruses, are enclosed within a membrane, which is derived from the cells they infect.  This membrane, composed of molecules called lipids, acts as a barrier to keep the contents inside (such as the viral genome) separate from what is outside.  Due to their properties, lipid membranes do not actively mix with each other.  For a retrovirus to get into a cell, it has to employ a protein that permits the intermixing of the viral membrane with the cell membrane – a fusion protein.  The fusion proteins reside on the outside of the virus and, after interacting with molecules on a cell membrane, allow the virus to spill its contents into the cell and start the infection process.

These fusion proteins are coded in the viral genome.  Thus, when a retrovirus integrates its genome into that of a cell, that cell can now produce the fusion protein. When a fusion protein gets to the surface of a cell, it can stimulate fusion with neighboring cells.  These fused cells now contain the contents of both progenitor cells and are known as syncytia.

To picture this, think of two beads of water running down a freshly waxed car during a rainstorm.  When the water droplets meet, they come together, forming a larger conglomerate with the insides now mixed between the two.  This is essentially what happens to form syncytia – the cells come together and mix their insides after induction by a fusion protein.

With so many viral genomes integrated into ours, our DNA contains many genes encoding retroviral fusion proteins.  Fortunately, most of these have been rendered inactive.  However, there is one exception in the placenta, an organ that is vital to the growth of a human fetus in its mother. The placenta seems to be a region where some of these fusion proteins are allowed to persist, and scientists now believe that these fusion proteins are not only active in the placenta, but also allow for it to function.

Viral helpers in the placenta

The placenta is the caretaker of a developing fetus.  It provides nutrients, eliminates waste, and shields the fetus from infection.  In fact, problems in the placenta generally lead to fetal complications such as growth restriction.  Thus, development of the placenta is imperative to life as we know it.

The placenta is a unique tissue that contains a specialized region that is involved in exchanging material between the mother and the fetus. It contains syncytia, or giant cells.  These syncytia are formed by the fusion of normal cells. When individual cells come together and fuse, they form a syncytium that contains the contents of both progenitor cells. This process can happen over and over, leading to a bigger syncytium each time.

It appears as though the cells of the placenta have usurped the virus-derived fusion proteins for their own advantage.  These proteins were later renamed syncytins for their ability to create syncytia (the giant cells). These syncytins are found not only in humans but also in most types of mammals that have a placenta – from elephants to mice.  In fact, studies in mice have shown that these syncytins are absolutely necessary for development of the placenta; without them, offspring cannot be produced (1).

Scientists think this principle holds true for all other mammals that have a placenta and syncytins – including you.  Since placental mammals originated over 100 million years ago, it is thought that there was one original syncytin in the ancestor to all placental mammals that has been replaced with others since that time.  This is an astounding example of how interactions with viruses could have paved the way for placental mammals to develop and proliferate

Researchers are continuing to search for syncytins in the genomes of placental mammals in which they have not yet been documented.  The most recent discovery was in marsupials (2).  Each time a new one is uncovered, it provides more proof that syncytins are a staple of placental mammals.

Unlikely benefits

Viruses, including many retroviruses, are most notorious for causing illness and death. However, without the acquisition of genomes from retroviruses, evolution as we know it may have been completely altered.  While viruses are often thought of as negative, the syncytins show that beneficial functions may come from the most unlikely (and potentially deadly) places.

From the example of retroviruses and syncytins, it’s clear that the relationship between viruses and humans is not as cut-and-dried of a situation as it seems. Undoubtedly, there is much more to understand about viruses and how they can influence our lives.

Joseph Timpona is a 3rd year virology PhD candidate in the Whelan lab.

References

1.  C. Lavialle, G. Cornelis, A. Dupressoir, C. Esnault, O. Heidmann, C. Vernochet, T. Heidmann, Paleovirology of ‘syncytins’, retroviral env genes exapted for a role in placentation. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 368, 20120507 (2013); published online EpubSep 19 (10.1098/rstb.2012.0507).

2. G. Cornelis, C. Vernochet, Q. Carradec, S. Souquere, B. Mulot, F. Catzeflis, M. A. Nilsson, B. R. Menzies, M. B. Renfree, G. Pierron, U. Zeller, O. Heidmann, A. Dupressoir, T. Heidmann, Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials. Proc Natl Acad Sci U S A 112, 96 (2015)10.1073/pnas.1417000112).

Further reading

http://www.mayoclinic.org/healthy-living/pregnancy-week-by-week/in-depth/placenta/art-20044425

http://phenomena.nationalgeographic.com/2013/05/10/the-lurker-how-a-virus-hid-in-our-genome-for-six-million-years/

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