HERVs vs HIV-1 and cancer-- Another step forward

If you are reading this blog, you already know all about how a huge portion of your genome is parasitic junk DNA (~40-45%), a fraction of which is retroviral junk (ERVs, ~9%).  If youre new here... SURPRISE!

Sure, we have a gene here, a promoter there (maybe) that was domesticated for human genome use, but its junk, and that is a good thing.  I mean, if our genome was 9% retrovirus and every one of them was active, we would all be dead from the insertional mutagenesis alone.

So your genome and cells have evolved lots of ways to make sure your junk DNA stays junk... but I guess ERVs are like zombies.  I mean, theyre dead, buried, portions of their previous genome have rotted beyond recognition... and yet when something has Gone Wrong, the ERV proteins (and some other junk DNA proteins) can rise from the grave.

There are lots and lots of human diseases that are associated with ERV expression-- lots of cancers, Multiple Sclerosis, ALS, even HIV-1.

Well... if junk DNA being expressed is a sign something is wrong... why dont we vaccinated against the junk DNA proteins?  What if you get this vaccine today, and kill the, say, the first breast cancer cells, before they ever have a chance to become a full blown tumor?

... Well?  Why not?

Because it could be a problem.  Almost half your genome is junk.  Which means a couple of things:

  1. Your immune system is trained not to harm 'self'.  The junk is 'self'.  Dang.
  2. The transcription and translation process is junky too-- Lets say there is a really active gene for microglial cells right next to an ERV.  By chance, you might make some junk ERV RNA, which goes on to accidentally make some protein.  A smidgen of an ERV, by mistake, might not cause any trouble on its own.  But if you have a ton of anti-ERV cytotoxic T-cells around, then we have a problem with autoimmunity.

Okay, well, still, the concept is very, very cool-- Why dont we at least try?

Vaccination with Cancer- and HIV Infection-Associated Endogenous Retrotransposable Elements Is Safe and Immunogenic

The potential vaccines candidates:

  1. LINE1 Open Reading Frame
  2. HERV-K gag (four versions)
  3. HERV-K env

Step 1, of course, is to see if these guys are expressed in healthy tissues.  You dont want a vaccine to prevent breast cancer lead to an autoimmune reaction that eats your lungs.  So they used panels of healthy tissue from humans, macaques, and mice to see if these guys are expressed anywhere.

gastrointestinal tract (tongue, salivary glands, stomach, duodenum, jejunum, ileum, cecum, and colon); endocrine organs (thyroid, pancreas, adrenal, and thyroid); skeletal muscle (gastrocnemius in mice and quadriceps in macaques); cardiovascular system (heart, aorta, and mesenteric arteries); skin; lymphoid organs (tonsil, spleen, lymph node, and thymus); bone marrow; central (cerebrum, including hippocampus and hypothalamus; cerebellum; medulla; pituitary; and spinal cord) and peripheral (sciatic nerve) nervous system; respiratory tract (nasal mucosa, trachea, bronchus, and lung); adipose tissue; urinary tract (urinary bladder and kidney); eye (retina); and liver from both sexes. The reproductive tract tissue list was as follows: female (ovary, uterus, cervix, vagina, and mammary gland) and male (testis, prostate, seminal vesicle, epididymis, and mammary gland).

On the bright side, out of all of those tissues, there wasnt a lot of reactivity in human tissue... but there was some, which means autoimmunity might be an issue.

Again, on the bright side, the results from humans mirrored the results from macaques, meaning vaccine trials in macaques might give us a really good idea of what kinds of side-effects to expect in humans.

Step 2 is working out how you vaccinate someone against a self protein.  It can be done, but your immune system really doesnt wanna.  They found that once they figured out what the most immunogenic version of the proteins were, a DNA Prime, Ad5 boost was the way to go (sound familiar?).

In macaques, they got a nice broad cytotoxic T-cell response, and the HERV-K Env was able to induce an antibody response.  If you prod your immune system enough, in the right way, you can break immune tolerance.

Step 3 is to wait.  If your immune system is attacking an organ, you will know it.

Turns out the vaccinated macaques were doing just fine:

Even in animals with the strongest immune responses, the tissues were morphologically normal.


We observed no histological evidence of disease induced by an immune response (vasculitis, glomerulonephritis, or retinitis) or by immune complex formation and/or deposition (vascular, glomerular, and ocular inflammation).


In summary, we observed no adverse safety effects from vaccination with ERE.

In fact, the macaques were doing so well, the researchers decided to go ahead and try to infect some of them with SIV to see what happens.  The results are in the pipeline for publication right now!  (!!!)

To sum it all up, a vaccine against an ERV might actually be a genuinely viable alternative therapy for some kinds of cancers/other diseases/HIV infection.

One mans junk is another mans life saving treatment!

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Dumb question that I could probably research on my own, but given that you're right here...

Say the macaque trails with SIV go well, and things are looking promising. With something like this specifically, what's the rough timetable for moving from nonhuman trials into possible human trials if everything goes peachy groovy at every step along the way?

By Optimus Primate (not verified) on 03 Jul 2012 #permalink

While cool, I see a number of problems with this. Expression of HERV genes (and even generation of viral-like particles) has been observed in a huge number of diseases, and AFAIK the signal regulating this expression seems to be inflammation and/or cell stress. Meaning, if we vaccinate against these HERV proteins, we may end up doing more harm than good. I.E. we could end up targeting any stressed/inflamed site, rather than specifically targeting a disease process. Since inflammation and cell-death are both normal and (usually) healthy, this could be bad.

That said, I think the potential in biologics (i.e. recombinant antibodies) is huge - if HERV expression can be shown to occur specifically in a disease-causing cell (i.e. an autoimmune cell), or in a diseased/infected cell, one could use recombinant antibodies to kill those cells. It would avoid the potential dangers of a vaccination leading to the targeting of all inflammatory responses, while still providing a way of selectively depleting the cells responsible for a disease condition.

Optimus: It rather depends on a number of factors, not least of which is the country in which the research is being conducted, but trials like this from start to market can easily be 10 years plus.

By Skepcheck (not verified) on 03 Jul 2012 #permalink

I see a potential problem that doesn't seem to have been addressed (disclaimer: I haven't read the paper yet). Using HERV proteins as antigens and not testing the expression in the placenta. What is the possibility that a vaccinated woman would be susceptible to a life time of spontaneously aborting her fetus?

By Poodle Stomper (not verified) on 03 Jul 2012 #permalink

Optimus-- Actually, they will probably have a lot of trouble getting it into human trials at all. The chance of autoimmunity would probably concern review boards a lot. I see them *maybe* being able to do it in cancer patients who have no other options, maybe progressed ALS or MS patients (but if the damage has already been done...).

Bryan-- Yup. Youre right. No weird effects in a healthy macaque doesnt mean there wont be autoimmunity after, say, a cold.

Poodle Stomper-- Good point. The vaccine was against a HERV-K, and syncytian is a HERV-W, so I would *think* that they are evolutionarily diverged enough (for instance, HIV is nothing like HTLV. antibodies vs one dont protect you from the other) that there would be no cross-reactivity, but they would have to test it.

In the light of HERV-W providing syncytin, is there any evidence for protective functions of HERV genes in humans that we might lose if we were to immunize ourselves against them?

ERV, looks like you're probably right. I ran a few alignments (b/c wtf not, right?) and it looks like they are pretty well divergent in terms of sequence. Good call.

By Poodle Stomper (not verified) on 05 Jul 2012 #permalink

Well I dunno. Years ago I read a book on the epidemiology of HIV and ir said that HIV infected cells couldn't make viral particles without CORTISOL in the soup suggesting that it might be long term persistent stress that turns on, not just retroviruses and retrotransposons, but also transposons and non retroviruses. (The stress of being out of kilter with the environment turning on genetic instability.) At the 19th International Genetics Congress a yeast lecturer described an experiment in which 10 times normal retrotrotransoposon elements were inserted into yeast cells without any negative effects on growth or reproduction. When I suggested that they were the number one evolutionary mutator he agreed. But when I suggested that it was time to stop calling them parasites he replied "I wouldn't go that far''.
Personally I reckon that we wouldn't be here without them as reverse transcription is a lot simpler than forward transcription, especially when you include splicing out introns and joining exons together with forward transcription So it had to have come first. What if, in the primordial soup, primitive RNA polymers interacted with primitive peptides, RNA somehow acting as template, peptide acting as enzyme. Catabolism during the day from sunlight and anabolism at night. Depolymerisation followed by repolymerisation. Yin and yang. But they can't go anywhere without building an archive, a library of DNA from which they can further mutate to make more genes by forward and reverse transcription once forward transcription arrives as happens with HIV. Make multiple copies of a protein until one fits and then reverse transcribe the RNA template, from which it was derived, to DNA and insert it into the genome with integrase upstream from the master gene from which it was derived. Introns added later. No monkeys needed.

By paul hill (not verified) on 08 Jul 2012 #permalink

I put a comma in the wrong place when I said in the above post
'forward transcription arrives as happens with HIV'.

In my original model using drug resistance in cancer cells, I had forward transcription of a gene for an enzyme that was not quite appropriate, then reverse transcription BECAUSE OF ITS INSTABILITY, ie inducing random mutations, followed once more by forward transcription, THEN translation. The resulting enzyme is tested for it's catalytic ability to deactivate the drug molecule. Not good enough, try again and again until one comes up which does the job. The template RNA for this enzyme is then reverse transcribed with reverse transcriptase to DNA which is integrated into the genome via integrase directly upstream from the master gene from which it was derived minus introns of course. This entire process is MODULATED by the degree of genetic instability in the cell caused by the drug.

Problem is, of course, reverse transcribing the new gene means it's likely to be mutated in the process and defective. But then why should reverse transcription be more unstable than forward transcription which is NOT proof read as is DNA replication. Does the presence of introns stabilize the transcript. Can't see how as they are only introns to the splicersomes AFTER transcription. Wouldn't the HIV RNA genome also be vulnerable when being reverse transcribed and integrated as DNA. However, it seems that only part of the genome is mutable, like the 'hypervariable loop', as if this instability is selective somehow.

Somewhere along the line I read that HIV is able to set up signalling pathways to various ion ports on the cells plasma membrane, thus increasing and decreasing the concentration of copper, zinc, etc. shifting pH and perhaps temperature up and down to achieve the instability of reverse transcription. Perhaps a retrotransposon can do this with FORWARD transcription when it takes control of a gene. This would eliminate two of the steps in the above model. Sounds far fetched, but so was the idea of reverse transcription to the 'CENTRAL DOGMA'. Thus spake Zarathustras Watson and Crick. Any suggestions?

By paul hill (not verified) on 08 Jul 2012 #permalink

No interest in evolutionary biology? Pity. I suggested once at a break up meeting of the Lorne Genome conference that, given the intimate relationship between nucleic acid and protein, wouldn't it be a good idea for the Protein and Genome Conferences to be combined, with speakers from each camp alternating. I was severely admonished by a convener who retorted with great vehemence, smoke bellowing from his nostrils, "That's be alright if we were looking for the origin of life. But we're NOT. This is APPLIED science." I cowered in fear under the seat, fully expecting to be dragged out onto the lawn and burned at the stake. You see, I was naive enough to think that understanding the origin of life might shed an itsy bit of light on how things work today. Any way I said 15 Hail Marys, stood in the corner with a dunces hat on for an hour and was fully redeemed. Until now that is, unfortunately.

By paul hill (not verified) on 09 Jul 2012 #permalink