Say youve got a problem. Maybe you cant figure out how to make a gene therapy vector that cant be detected by pre-existing antibodies that everybody already has. Maybe you are trying to figure out how to make an effective HIV-1 vaccine.
You could figure out which portions of AAV or HIV-1 are really important, try to make point mutations here and there, trying to get the virus to do what you want it to do… Or you could just let evolution do all the hard work for you– Letting random mutation and natural selection identify a variant that can perform the tricks youre after.
A lab has already done that with AAV. They started with ‘diversity’ and used evolution to identify gene therapy vectors that could target brains, livers, lungs, etc, and CANT be recognized by pre-existing antibodies.
Now another lab has caught onto this cool idea to help make better HIV-1 vaccines!
This lab is starting from a different angle. Instead of starting with diversity and having evolution narrow possibilities down to one/a few variants, this lab is starting with one variant, and letting random mutation and natural selection generate lots of different solutions!
So here is the problem– We cant figure out how to make a vaccine against HIV-1 that generates lots of ‘broadly neutralizing antibodies’, antibodies that can still recognize viruses if they mutate away from what was put into the vaccine.
We can make slightly better vaccines if we chop up env a little bit. If we cut out two really variable regions of env, the Variable 1 loop and the Variable 2 loop, we can make higher affinity antibodies to neutralize viruses, because your immune system can focus on a REALLY important region of env, the Variable 3 loop.
It would also be really cool if we could make envelope trimers that can be excreted by cell lines, so we could just throw them into a vaccine instead of dummy viruses. It would be a LOT easier to make huge quantities of secreted protein, rather than purifying delicate dummy viruses… but if you chop out V1/V2, the secretable Env trimers we have just dont work.
SO! This lab created a whole bunch of potential V1/V2 deletion variants by deleting this region in a few different ways. All of these variants just didnt work as well as a nice wild-type envelope protein. So they took a population of each variant and repeatedly passaged them in T-cells for four and a half months (!!!). Their logic was that even though their V1/V2 deleted viruses were ‘crippled’, the populations would accumulate compensatory secondary mutations to regain their replicative capacity. We know HIV-1 can do this, because thats exactly what happens with HIV-1 drug resistance– Initial mutations to escape antiretrovirals come at a fitness cost, but over time, compensatory mutations lead to a virus that is super fit AND can escape the antiretrovirals. So why not use HIV-1s evolutionary abilities to generate a weapon we can use against it!
At the end of 4 1/2 months, some of the populations konked out. The viruses were crappy at replicating, and eventually went extinct. But some populations got better at replicating, AND more stable… which means they are not only better for making antibodies, they are also better for generating those secreted envelope trimers for vaccines!
Now, this doesnt mean that we will have an HIV-1 vaccine in 2 months.
It doesnt mean that any of the clinical research that comes out of this particular study will eventually end up in a vaccine.
But, its a new tool. Its a new weapon we can at least try against HIV-1.
And we got it by using evilution.