Your immune system is like an
onion ogre parfait.
Its has lots and lots of layers.
You have intrensic immunity– Abilities every single one of your cells has to defend itself from viruses.
VpuTetherin would be a good example of this, as would APOBEC and Trim5a. Pick a cell in your body– it can make these proteins. Doesnt have to be a special immune cell.
Then you have innate immunity– Certain immune cells are not specific for any particular pathogen, but they can identify patterns that are ‘wrong’. They see things your body knows aint right, like double-stranded RNA (your body doesnt make that!) or unmethylated bits of DNA made up of mostly Cs and Gs (your body doesnt have that!), or bacterial proteins like flagellin (mammals dont have flagella that look like bacterial flagella!). These cells dont care what virus is making the double-stranded RNA (HIV-1, rotavirus, respiratory syncytial virus), it just knows that double-stranded RNA is wrong, and that happens to be a step in these viruses life-cycle. Only immune cells can see pathogens this way, and respond accordingly.
And then theres adaptive immunity– This is the one you all are probably most familiar with. These immune cells evolve in the face of infection to be specific for that pathogen. Very generally, Cytotoxic T-cells evolve to specifically target and kill host cells infected with the pathogen, and B-cells evolve to make antibodies specific for the pathogen, to neutralize them or make them easier for your immune system to see–>kill.
All this specific immune response takes time to evolve (couple weeks). Viral vaccines use weak/dead viruses to prime your adaptive immune response. Thus when you are exposed to a real, harmful virus ‘in the wild’, your body has a cheat-sheet for how to get rid of the virus. Your response is stranger and faster than if you had never gotten the vaccine.
To bring this back to HIV-1, we might be screwed when it comes to making a CTL vaccine (or, if we dont do it quick we are screwed). HIV-1 is figuring out how to pick our locks at a population level.
Okay, well, what about antibodies, then? What about a vaccine that revs up B-cells instead of T-cells?
Well, a series of papers have been coming out of a lab in the Netherlands that makes me think we might be screwed on that front too.
And once again, its all evolutions fault.
So heres The Problem: Lots of people who are infected with HIV-1 make nice cross-reactive neutralizing antibodies (their antibodies dont just work against the subtype of HIV-1 they are infected with, but other subtypes as well).
These antibodies are not enough.
Everyone still progresses to AIDS after infection. Slowly, quickly, everyone eventually gets AIDS.
So, either these neutralizing antibodies fade with time, or HIV-1 is evolving to get away from the antibodies.
Its not the former– all the patients used in these studies have great cross-reactive neutralizing antibody responses.
Its the latter. HIV-1 evolves to escape these antibodies… and your body cant catch up. It keeps making the old antibodies, making antibodies to viruses that were in your body months… years ago… When those viruses are long gone. HIV-1 evolved away from them.
Now, theoretically this would be A Good Thing. HIV-1 can escape CTL responses. It comes at a fitness cost. HIV-1 can escape drugs. It comes at a fitness cost. So HIV-1 escaping from antibodies should come at a fitness cost…
Except it doesnt (I would argue that these papers dont measure ‘fitness’. they technically measure replicative capacity. unless there are gross deficiencies in any of their isolates, they wont be able to see small fitness differences, but I digress).
What this means, is, the absolute opposite of everything and anything you have heard a Creationist tell you about how proteins evolve. They say that you make a mutation here, you make a mutation there, and suddenly, things dont work anymore! Wow, isnt that protein PERFECTLY DESIGNED!
In the case of HIV-1 Envelope, not only is there massive genomic and protein sequence variability, but this variability translates into functional plasticity. Envelope can change a lot, and still work fine and dandy. Envelope can change a lot and these changes do not come at a fitness cost.
HOW THE HELL CAN IT DO THAT?????
This all just means that making an HIV-1 vaccine to elicit antibodies is going to be a tough road… *sigh* Deeeeebie Downer…..