This idea... this idea might be absolute genius...
The 'best' vaccines are live attenuated vaccines. Weakened/Misadapted viruses that can replicate a little bit, and get your immune system to generate a B-cell response (what you get with most vaccines) and a CTL response (what you really need a 'live' virus for).
But with some viruses, it isnt practical/possible to make an attenuated version (think HIV-1. aint nobody ever going to get an attenuated HIV-1 vaccine unless something radical changes), or even if it is, federal regulators might be too 'scared' of it (like with an attenuated HSV-2 vaccine).
So scientists have figured out 'tricks' for inducing CTL immunity outside of a live attenuated virus. We REALLY want one in HIV World, because we think how well your CTLs respond to the initial HIV infection plays a role in how quickly you progress to AIDS. So scientists have tried things like making an adenovirus deliver HIV proteins, which CTLs could respond to... and that did not work out as planned :-/
This group of scientists is trying something different, with another virus that isnt a likely candidate for a live attenuated vaccine, HPV. And like I said before, I think it is ridiculously clever.
One of the HPV vaccines on the market is Cervarix. It protects people from two variants of HPV that can cause cancers, 16 and 18. And it works great.
But these folks wanted to use it as a model to see if their approach might make a different (better?) vaccine.
They made baculovirus (remember these guys? helping us with the vegan situation?) that 1) would express a human endogenous retroviral Env when in insect cells, and 2) express HPV-16 and -18 proteins when in human cells.
From the HPV perspective, the resulting pseudovirus (part insect virus, part ERV, delivering HPV 'goods') worked just as well as Cervarix at inducing B-cell responses, and it protected mice just as well from HPV challenge, AND it came with the added bonus of inducing CTL immunity. Because the ERV Env is on the outside of the pseudovirus, it allows the vaccine virus to infect cells and generate the necessary endogenous HPV proteins from within a cell, a necessary step for CTL responses.
So, proof-of-concept of their scheme worked!
But heres where its GENIUS-- from the ERV perspective.
1-- People should not have, or generate, antibodies to a human endogenous retroviral Env. The stuff in your genome when you were developing is YOU, according to your immune system. Throw these guys into a vaccine, and your immune system *should* ignore them entirely! This lets the viruses deliver their cargo unperturbed, AND it might mean that you could do numerous vaccines using the same system-- A baculovirus HPV vaccine, a baculovirus HSV vaccine, a baculovirus HIV vaccine, antibodies to the vector shouldnt interfere with you getting the immune response you want, because the antibodies arent there!
This also could have implications with gene therapy! You cant use the same gene therapy vector too many times, or your antibodies will simply neutralize the vector before it can deliver the goods. Not a problem when an ERV is on the surface, though! Its YOU!
2-- Lets say this approach becomes The Go-To approach for EVERYTHING. Tolerance to self can be overcome (autoimmunity), so maybe eventually the approach stops working because the patient developed anti-ERV-Env antibodies. Oh no! Vaccine/Gene Therapy induced autoimmunity!!!
... Who cares!! ERV Envs are not normally expressed on healthy tissue! In fact, Env expression has been associated with any number of diseases! Developing immunity to Env might have some unintentional beneficial consequences, like decreased risk of certain cancers!
I like this paper.
If ERV Env isn't expressed in tissues, how do they induce negative selection? Are they expressed in the thymus?
Thats something that confuses me too. In the diseases associated with ERV expression, *sometimes* there are also anti-ERV antibodies, and I dont know whether that is from a regular response or its from overcoming tolerance. Hey lets ask Edward over in the other thread!
ERV is expressed in the thymus. "Negative thymocyte selection to HERV-K18 superantigens in humans"
I found that paper a couple of days ago because I was thinking HERVs would be great for doing a nonimmunogenic vaccine vector, cuz they're self. I am almost crying now.
It is possible to induce immune responses with ERV proteins, as well as LINE-1 orf2. http://www.ncbi.nlm.nih.gov/pubmed/22745376
They didn't see any resulting pathology, at least according to the abstract (haven't had a chance to get the whole paper.)
The env gene they used was syncytin-1, and looked like it's well-conserved in people. Unlike most rv or erv envelope proteins, it has a nonfunctional (at least in mice) immunosuppressive domain.Homology between syncytin-A (mouse) and syncytin-1 is ~40% with ~15% gaps if I BLASTED right. I'd like to see the immunogenicity of a mouse syncytin-A peudotyped vector for comparison.