HERVs and HIV-1

Quick recap of ERVs for new readers of ERV (or long-time readers who have forgotten!)--
ERVs are retroviruses that accidentally infected an egg/sperm cell, and became a permanent part of that egg/sperms DNA. That egg/sperm then went on to successfully generate a viable embryo, and because that retrovirus was part of the egg/sperms DNA, it also becomes a permanent part of the organisms DNA.

Though this is a very very rare, totally accidental event, on an evolutionary time-scale, random events have happened quite a few times, to the point where a large chunk of your, *your* DNA, is unquestionably retrovirus.

But retroviruses are A Bad Thing. They make us sick. Duh. So why arent we all sick now?

Well your genome has evolved ways of keeping these retroviral elements quiet-- they are *there*, but they arent making babby viruses. The ERVs eventually accumulate lots of deletions and mutations, so they couldnt even potentially maybe generate a virus... but some of the younger ERVs still have the ability to make retroviral proteins, if not entire virus, if the cells tricks to keep the viruses quiet arent working properly.

Because ERVs are normally quiet, it seems looking for ERV proteins might be a useful marker for disease-- cells arent working right because of cancer or some disease state, cells are not controlling ERV expression anymore, presence of ERV proteins indicate a disease state.

But its not just cancer or ALS that might throw a cell out of whack so ERV elements are activated... It looks like HIV-1 infection can do the same thing. Before:



Characterization of Human Endogenous Retroviral Elements in the Blood of HIV-1 Infected Individuals

HERV-K elements are the youngest ERVs in your genome. If you poke cells in just the right way, you can get particle formation from totally normal, healthy human cells (but theyre noninfectious... probably). But a normal healthy human usually has fewer than 100 copies of HERV-K RNA/ml of blood (junk RNA from leaky/accidental transcription).

Breast cancer patients can have up to 108 copies/ml.

HIV-1 patients have up to 1010 copies/ml. O.o

Thats not just junk RNA, either. This group looked for HERV-K proteins and actual viral particles, and found them in the HIV-1 positive patients. Furthermore, the active HERV-Ks they found in the breast cancer patients all kinda looked alike. Continual transcription-->translation from the same endogenous retroviral locus. Like a factory that only knows how to make one toy.

... The HERV-K sequences in the HIV-1 patients changed over time. They were not just being transcribed-->translated... they were actively reverse transcribing and replicating... mutating and undergoing selection. That has never been described with a human ERV before O.o And it turns out that some of the activated HERV-Ks were human specific (ie not found in chimpanzees), which makes it look like these guys are still young and potentially active in humans!

And, this situation isnt as simple as 'In breast cancer, THIS HERV-K is activated!' or 'In HIV-1 infection, THIS HERV-K is activated!' They found 34 different activated HERV-Ks in their patients, six of which had never been described before. One, K111, was only found in the HIV-1+ patients, not the breast cancer patients.

But what does this all mean?

Well, for some kinds of breast cancer, this might mean we could figure out a diagnostic tool out of this. These scientists did *not* look for HERV-K expression in breast cancer tumors. They looked for HERV-K expression in blood. But, the question is, does the HERV expression only pop up after the cancer is already established and causing trouble (thus not a lot of help to us), or might they pop up way before things get really bad (thus giving us an extremely non-invasive diagnostic test?).

With HIV-1+ patients, this might mean we have a non-HIV target for our anti-HIV efforts. If these HERV-Ks are upregulated in infected cells (we dont know, it might be a global phenomena in response to an activated immune state, thus useless), we could direct our therapeutic vaccination efforts there. Target the old HERV that is not changing (... much...) instead of the rapidly evolving HIV-1.

Very very cool info in this paper. Maybe retroviruses that inserted into our genome, by accident, tens of thousands of years ago, can help us deal with modern diseases!

... Or they might be an artifact of the disease. Too little too late to be of any use to us. LOL!

We wont know until we look!!

More like this


Very interesting. Can you give a layperson's overview of what sense and antisense transcription is please? At what point and after what additional research steps would scientific consensus establish that a newly recognized active human retrovirus is in the wind?

HERV-K research has been going on for many years. Is there a particular turning point that could establish the difference between recognition of a disease-causative microbe as opposed to the presence of incidental "junk" DNA? If so, what would be a typical time line for commercial serology tests?

Question about HIV reagents: can you FACS sort on cells that are expressing HIV env proteins on the surface?

It would be awesome if you could sort out env+ cells from env- cells and see if either population is actually expressing these HERVs.

@Levi The terms "endogenous", "exogenous", "epidemic" and "endemic" are very frequently misunderstood and misused even by researchers who should know better. The terms "homologous", "homology", "similar" and "similarity" are also very often mis-used as in "The sequences showed 87% homology to each other." On top of this, there is most often no identifiable single moment when a virus goes from exogenous to endogenous or visa versa. A retrovirus getting into a germ cell (sperm or egg) and integrating into the DNA is one step, but the birth of a child from the infected germ cell and then subsequent generations passing the enogenous virus on until fixation in the population of host individuals is reached, are other important steps.

Likewise, going out of the endogenous state, it is one thing to produce a viral particle, another step for that particle to be able to infect another cell in the same host, and yet another step for the virus to be transmitted from one host individual to another. Human pig farmers get infected with swine flu quite often for example but almost never pass it on to other humans. Human zoo workers often get infected with simian foamy viruses but the infections do not spread to other humans in contact with those zoo workers.


I usually enjoy your blog, but have you really read this paper closely? I would recommend reading the 2007 AIDS Res & Hum Ret paper from the same first author, specifically figure 4. I feel like I've seen this song and dance before...

Hey Abbie, cool post - it's good to see some ERVs back on ERV. Have you thought about putting this - or any of your work - up onto December's Molecular Biology Carnival (http://molbiocarnival.blogspot.com/)? I am hosting it over at Ruleof6ix and thought this kind of stuff would be excellent!

How much is known about the mechanisms cells use to prevent ERVs from being translated? My first assumption would be that HIV needs to turn off some of those mechanisms in order to reproduce itself. That would mean there's a potential new class of antiretroviral drugs.

Yes, this is old news but it is new to me. If it weren't for HERV-W 100nm exosomes spit out of the placenta, homo sapiens would not be around. These HIV sized exosomes are immunosuppressive where immunosuppression is needed and also where it is not needed such as in cancer. Cancer cells spit these exosomes out that go to sentinel lymph nodes and turn them off. They are a good process gone awry. HERV exosome production can be induced by chemicals such as the AML drug AzaC. I'm sure you know how to turn them off at the CpG site of the LTRs. Strangely enough, HIV may also be induced and turned off. It doesn't get constitutively cranked out. The weirdest thing to me is that CD45 purified HIV particles are a potluck stew of host cell proteins not just membrane. When you look at two identically sized HIV particles, they contain totally different host cell proteins. So to a lot of people, HIV are also exosomes. HERV exosomes from tumors are immunosuppressive on their own, and there is no need to invoke a killer overnight slow retrovirus that takes 10 years to kill you that is just like HTLV-1 and suppresses your immune system like mycoplasma does. Unfortunately, fertility is dependent on germ line HERV, so who knows what tinkering with HERVs will do to human fertility. What do you think about the co-factor hypothesis?

By ERV curious (not verified) on 17 Jan 2012 #permalink