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New research: Env-less endogenous retroviruses are genomic superspreaders

natasa778

Senior Member
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1,774
From Discover magazine blog

... By looking at IAPs across 18 species, Magiorkinis found that those that lost their env were also far more abundant. This loss doesnt just reflect the normal genetic wear-and-tear that happens with time. In many viruses, env broke down even though other viral genes were intact. And this process only goes in one direction. ERVs often lose env and spread like wildlife, but those without the gene never regain it.

This trend isnt restricted to IAPs. Magiorkinis searched for other ERVs among the genomes of 38 mammals, including mice, bats, elephants, and more. Of the many families he found, almost all the most abundant ones had lost or degraded their copies of env. The viruses had repeatedly invaded genomes, lost the ability to spread across them, and become many times better at spreading within them.

You can think of the rise of ERVs as an epidemic thats confined within a single genome, and plays out over millions of years. This isnt just a cute metaphor. Magiorkinis found that the biggest 20 per cent of the ERV families accounted for 80 per cent of the total sequences. This distribution is remarkably similar to the 20/80 rule in epidemics, where the most infectious 20 per cent of infected individuals account for 80 per cent of transmissions.

Why should the loss of a single gene make so much difference? Its possible that env might harm the health of the viruss host, either by allowing the virus to infect more cells, or by directly weakening the immune system. By losing the gene, the virus might get a longer-lived carrier, and more chances to be passed on to future generations.

Alternatively, spreading within a genome might just be a more efficient way for the virus to copy itself. It doesnt need adaptations that allow it to survive outside of cells, or avoid defences that target its coat proteins. By hanging up its coat, it might get an easier lifestyle.

Whatever the reason, its clear that this shift is a successful strategy. ERVs have been found in every mammal genome, and they have been our passengers for millions of years. By losing the ability to infect, they could truly go viral.

Original article:
Magiorkinis, Gifford, Katzourakis, de Ranter & Belshaw. 2012. Env-less endogenous retroviruses are genomic superspreaders. PNAS http://dx.doi.org/10.1073/pnas.1200913109

We thus borrow simple epidemiological and ecological models and show that retrotransposition and loss of env is the trait that leads endogenous retroviruses to becoming genomic superspreaders that take over a significant proportion of their host's genome.
 
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By hanging up its coat, it might get an easier lifestyle.

Whatever the reason, its clear that this shift is a successful strategy. ERVs have been found in every mammal genome, and they have been our passengers for millions of years. By losing the ability to infect, they could truly go viral.

Very interesting, thanks Natasa. It's a thought-provoking piece, but I wonder if they are rather missing the point here? It seems kind of obvious to me that the loss of the ENV would define a point at which the virus gives up its 'self' (when it's 'defeated' as an independent and threatening entitiry, and the process of its assimilation begins) and that it would naturally become more widespread at that point.

When we discussed retroviruses and ERVs here a year or two ago, one of the 'big ideas' that caught my attention was the concept that retroviruses might be the true drivers of biological evolution (at the microscopic level). The process by which a virus becomes endogenous suggests that organisms (viruses) start out as pathogens (outsiders) but eventually become integrated into the human genome (they are 'absorbed') and perhaps that process is fundamental to how complex organisms evolve their complexity - by ultimately co-opting all successful invaders.

So against that background, it seems to me that the loss of the ENV (thinking of the ENV as the 'shell') defines a point at which the organism "hangs up its coat" (as the text has it) as a separate organism, and transitions to 'merely' a sequence within the host. So yes, at that point it has become more widespread; in that sense this 'death' of the organism (as cell) but the survival of the cell's interior is really a success story; it has proved itself so successful an 'outsider' that the best way for the 'inside' to deal with it is to co-opt it.

This reminds me of the "alternative medicine" vs "science-based medicine" distinction - the most successful 'enemies' must be absorbed and their strengths must be learned from, and then they become "medicine" rather than "alternative medicine" - "endogenous parts of the organism" rather than "viruses". And the loss of the "shell" (ENV) is a defining stage in this process for the cell. In the analogy with "science-based medicine", "science" is the body - the dominant organism which by definition regards alternative ideas as "outside" and disparages them...right up until the point at which they cannot be defeated and are thus proven and absorbed. 'Science' remains dominant after the absorption, but should perhaps have a degree of humility when dealing with everything 'outside' and recognise that it is itself composed entirely of ideas that were once 'outside' itself.

We're accustomed to making this distinction between one thing and another, between the inside and the outside. But those fundamental assumptions break down precisely at this evolutionary point where the outsider is absorbed and becomes a part of the inside - and this process causes us all kinds of confusion if we don't recognise that what we normally tend to think of as sharp lines are really permeable boundaries.
 

anciendaze

Senior Member
Messages
1,841
I would like to apply some of these insights to a retrovirus we've all heard about, XMRV. Both components of this were said to be fully endogenized prior to recombination which created an active virus capable of infecting human cells. One such component was found in the samples tested, the other was either not found or not sought, depending on who is talking. A very similar sequence may have been present in a virus isolated in 1974, long before the proposed recombination event.

The presence of IAP sequences has been taken as an indication of contamination by mouse cells. IAP sequences are common in other species with long-term retroviral infections. A virus similar to an MLV persisting in a human for 15 years is like a virus infecting mice for many generations. It is not at all unreasonable that it might begin the process of becoming endogenous in somatic cells even if it did not insert genes in germ-line cells. The distinction between IAP sequences resulting from contamination and those resulting from endogenization is more subtle than sometimes declared. Large numbers of distinctively murine sequences do show contamination, but we don't really know what sequences would result from long-term infection by gamma retroviruses in humans.

What is missing from various nucleic acid sequences for XMRV is the sequence coding for the envelope. This has been extrapolated backward from the sequences of resulting proteins. There is circular reasoning in attributing this to a mouse virus, "since we know there are no corresponding human gamma retroviruses." If you are going to use this as an axiom all the rest of your research on putative human gamma retroviruses is mere window dressing.

The envelope is the key to the presence or absence of a retrovirus capable of infecting humans. Research by T. Heidman et al. even resulted in a patent on an immunosuppressive domain in the envelope, which would be a useful target for antibodies. Beyond entry through the XPR1 receptor, which the mice in question lack, later research shows the virus studied in laboratories has the ability to infect some cells without that receptor, and that shortening the tail that penetrates the cell membrane can result in syncytium formation, an aspect of some common pathologies of infectious diseases. These multiple adaptations crucial to the question of infecting human cells and causing disease remain completely unexplained.

The envelope in question could be the result of pseudotyping. If so the active virus contributing this envelope should be of extreme interest to anyone concerned about infectious diseases in humans. Where did this envelope, with its multiple adaptations, originate?
 

natasa778

Senior Member
Messages
1,774
Thanks ancientdaze! Yes this seem VERY relevant
(I heard this on radio first and env pseudotyping was the first thing that sprang to mind...)

Maybe thread should be moved to xmrv section?
 

anciendaze

Senior Member
Messages
1,841
...Maybe thread should be moved to xmrv section?
That appears to have become a kind of ghetto. What I'm suggesting in that sentence quoted by lansbergen is that the virus infecting humans is not the one currently defined as XMRV.

I've already noted that some of the primers used in searching for XMRV, and possible HGRVs, cross the deletions which have been chosen by critics as defining characteristics of XMRV. Deletions can happen very easily by RNA interference, or even mechanical instability of a sequence. In a retrovirus, deletions in RNA can be quickly converted to DNA. Other putative human gamma retroviral sequences without these deletions are already in genbank. To find those sequences, while also testing for XMRV, you would need degenerate primer sets. The problem here is that it is difficult to design such primer sets without actually detecting something that will spur further research. Critics have repeatedly declared such research a waste of money, even in advance of actually doing any.

For those who insist that defining the deletions as essential was unbiased science choosing "highly-conserved" sequences to search for I present this relevant example.