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Junk No Longer: ERVs Are “Integral” and “Important Components” of Immune Responses

Image credit: lisichik, via Pixabay.

Viruses and immunity are hot topics these days, and a new article in the Journal of Virology, “Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections,” has the potential to be a paradigm-shifter on the standard view that endogenous retroviruses (ERVs) are junk DNA. Consider this first line from the abstract. Though the authors are certainly not supportive of intelligent design, (ID), it’s another example of a line from a paper that sounds like it could have been written by a proponent of ID:

Long disregarded as junk DNA or genomic dark matter, endogenous retroviruses (ERVs) have turned out to represent important components of the antiviral immune response.

Smitha Srinivasachar Badarinarayan and Daniel Sauter, “Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections,” Journal of Virology, 95(12): e02299-20 (June, 2021)

Defeating Two Arguments

ERVs have long been a go-to argument against ID from those who believe that our genomes are full of undesigned junk. An outgrowth of this view is that ERVs have no functional importance, and that shared similar ERV sequences in similar genomic locations across different species (e.g., humans and apes) indicate their common ancestry. After, goes this way of thinking, ERVs were clearly not put there for any purpose. 

If this paper is correct, however, then ERVs frequently have important immune functions and they should not be presumed to be “junk DNA.” This defeats both the “junk ERV” argument against the design of the genome (human and otherwise). It also challenges those who want to use the supposed junk-status of ERVs as an argument for common ancestry. After all, if ERVs have functions, then shared ERV sequences in similar locations across genomes of different species may reflect functional requirements rather than mere common ancestry. 

More Narrative Gloss

To be sure, the authors of the paper don’t see their results as defeating any evolutionary arguments. The subsequent sentences of the abstract immediately put a spin on ERVs — what we’ve in the past called a “narrative gloss” — to interpret them in an evolutionary context: 

These remnants of once-infectious retroviruses not only regulate cellular immune activation, but may even directly target invading viral pathogens. In this Gem, we summarize mechanisms by which retroviral fossils protect us from viral infections. One focus will be on recent advances in the role of ERVs as regulators of antiviral gene expression.

The article continues with the narrative gloss, saying that some 8 percent of the human genome “represent[s] remnants of once infectious exogenous retroviruses that became fixed in our DNA” and that “the host cell has coopted fossils of possibly once harmful retroviruses to limit the spread of current viral pathogens.” So despite evidence for function of ERVs, we still see language suggesting that the only way to view them is that they were placed where they are by unguided mechanisms of viral insertion (e.g., “remnants of once-infectious retroviruses” or “retroviral fossils”). That’s one interpretation — and perhaps in some cases it is true. But the raw data — what we can directly observe and which is the focus of this paper — shows “important” immune functions for ERVs as regulators of gene expression and immune system activation. The article explains:

[M]any ERVs are not detrimental and have … important physiological functions in the host. Besides well-known examples, such as syncytins that regulate placental development, ERVs have become integral parts of immune defense mechanisms and help to fight off invading viral pathogens

Eight Mechanisms of ERV Functionality

Let’s dig into some of those mechanisms and the evidence for ERV function in the paper. It starts with a very useful diagram illustrating eight different mechanisms of ERV functionality:

Figure 1 of Smitha Srinivasachar Badarinarayan and Daniel Sauter, “Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections,” Journal of Virology, 95(12): e02299-20 (June, 2021), used under Creative Commons 4.0 International License. Not intended to imply endorsement by the authors.

Using the letters for each subfigure in the diagram above, we see that ERVs work to initiate immune responses to viruses in a variety of ways:

(A) ERVs use “viral mimicry” where ERV-encoded long non-coding RNA (lncRNA) molecules bind with viral RNA to activate pattern recognition receptors (PRRs) which activate an immune response. 

(B) LncRNAs produced by ERVs can also induce expression of antiviral cytokines, creating a “positive feedback loop enhancing antiviral immune responses.” 

(C) Proteins encoded by ERV DNA can also enhance immune responses by binding with toll-like receptors.

(D) ERV envelope proteins (called ENVs) are the outer layer of viruses which protects the genetic material inside. ENVs can bind to receptors which harmful viruses might use to enter host cells, blocking them from entering. 

(E) ENV proteins can enter viruses themselves and interfere with the viral life-cycle, inactivating viruses before they infect new host cells. 

(F) ERV proteins can also stop viruses by interfering with viral capsids that have already entered host cells. 

(G) Some ERVs that are neither transcribed nor translated can promote recombination which increases the number of host genes that can be used to target viruses. This is an evolutionary mechanism, but it could explain how ERVs can be a built-in designed mechanism to increase immune responses within a species.

(H) There are also very important ERV functions for regulating gene expression, as ERVs can act as promoters, enhancers, or transcription start sites for gene expression. The article explains just how common this is:

This cooption of regulatory elements is not a rare phenomenon, and it has been estimated that about 20% of all transcription factor binding sites in humans are found in HERVs and other transposable elements. In line with this, a meta-analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data sets identified about 800,000 transcription factor binding sites within HERVs. 

Intriguingly, almost 90% of all HERVs represent so-called solo LTRs [long terminal repeats, which can serve as binding sites to regulate gene expression]. These HERVs lost the prototypical retroviral genes gag, pol, and env due to homologous recombination of their flanking LTR sequences, leaving single LTR promoters in the genome. Due to their activation upon immune stimulation, ERV LTRs have already been termed “landing strips for inflammatory transcription factors” (90), and evidence for their role in regulating cellular immune responses is growing.

If you read that carefully, 90% of ERV sequences don’t even resemble full or true “endogenous retroviruses” because they lack standard ERV genes (i.e., gag, pol, env) and simply represent long terminal repeats which can serve as binding sites for initiating or enhancing gene expression. This strongly suggests that not only can “ERVs” have function, but that some 90 percent of ERVs don’t even resemble actual “endogenous retroviruses” and may not deserve to be called “ERVs.” They are simply functional stretches of DNA in our genome used to regulate gene expression. 

The article finally discusses an area for future research — ERVs may help fight cancer:

Finally, cancer research has already demonstrated that artificial induction of ERV expression can boost antitumor immune responses, and it will be important to investigate whether similar beneficial effects can be achieved for the therapy of viral diseases.

“ERVs” as Designed DNA Rather than Retroviral Insertions

From the evidence reviewed above, what we see is that not only are ERVs “important” and “integral” functional parts of our immune system for fighting off viral infections, but up to 90 percent of “ERVs” don’t even resemble true “endogenous retrovirus” sequences. They may show some similarities to true “endogenous retrovirus” DNA — but these similarities might be related to their function of fighting off viruses, and are not necessarily due to some ancient viral insertion. 

Perhaps some of these ERV-like sequences do reflect ancient ERV viral insertions, but it’s also possible that what evolutionary biologists call “endogenous retroviruses” frequently aren’t actually ancient viral “fossils.” Indeed, that very view of “ERVs” as ancient viral insertions may be what caused them to be “long disregarded as junk DNA,” as the paper puts it. 

Thus, perhaps DNA sequences that are often called “ERVs” often did not originate as viral insertions, but were intelligently designed as vital parts of our genome which play important immunoresponse roles to viral infections. Under this view, the reason these ERV-like sequences resemble (to one degree or another) viral DNA is because these similarities are required for their functional role to mimic or interact with real viral DNA during an immunoresponse. This is an intriguing new way to understand “ERVs” — not as viral fossils, but as vital components of our immune system.