It’s well known that HIV mutates rapidly in infected patients in order to escape from the immune system. The mutations in HIV track with the peptides that bind to MHC class I in any particular patient. When the virus is transmitted to a new patient, though, those mutations don’t help it much, because MHC is so variable between individuals that the new infected person will very likely have a different MHC class I pattern. (In fact, the mutations the virus developed in the first patient, are likely to be actively harmful to the virus.) The virus has to start all over again and discover a new path toward immune escape. Over a long enough time, the virus may be able to slowly accumulate mutations that allow it to escape from the worst of the MHC class I alleles (see here for a possible example), but it’s very difficult, simply because MHC is so diverse.
But MHC class I itself is only the final stage of a longish pathway of antigen presentation — the route by which peptides are produced, modified, transferred into the right location, bind to the right proteins, all that stuff. (If it’s slipped your memory a little, I made a summary page for MHC class I antigen presentation here.) Within that pathway, at least in humans, it’s only the MHC class I heavy chain itself that’s wildly diverse; the other steps are pretty similar between any two individuals. So why doesn’t the virus mutate to avoid one of these monomorphic steps, and then not have to worry about re-mutating all over again after the next transmission?
Putting that less teleologically, why don’t mutations in HIV, that allow it to escape from the monomorphic steps in antigen presentation, persist in each new individual and accumulate within the population? Those mutations should be just as beneficial to the virus in the new infected person as in the original infectee.
Rob de Boer’s group asked this question recently,1 and found that
… within hosts, proteasome and TAP escape mutations occur frequently. However, on the population level these escapes do not accumulate … 1
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| TAP structure2 |
(My emphasis) And the reason is the same reason other immune escape mutations don’t easily accumulate in the population: MHC is too diverse. If I follow the argument correctly, because the other components of the system are monomorphic, they have a very broad specificity for peptides, whereas MHC itself has a fine specificity. The virus can’t mutate every possible sequence in its genome that would interact with, say, TAP, because there would be thousands of them. If a mutation that prevents TAP binding does arise in one host, it’s selected because it prevents recognition of a particular MHC class I-binding peptide, and when it moves into a new host that peptide is no longer relevant for immune escape, so it’s not selected any more.
That means that, even taking the whole antigen presentation pathway into account:
The total number of predicted epitope precursors and CTL epitopes in a large population data set of HIV-1 clade B sequences is not decreasing over time. 1
I am a little cautious about accepting this paper completely, because it’s heavily based on database analysis without a lot of testing; we don’t actually know whether the escape mutations they identify for TAP actually do escape TAP, for example. They make a number of arguments, in passing, for the accuracy of the epitope prediction programs out there; I am slowly backing in to some acceptance of the notion that the predictive programs are getting pretty good, which wasn’t my position a couple of years ago, but I still am not convinced they’re as good as they say here.
But the conclusion is fairly simple and straightforward, and it leads to an interesting suggestion:
… we speculate that only one of the steps in the antigen presentation pathway has to be polymorphic to prevent pathogens from adapting to any step in the pathway. The mechanism functions best when the polymorphy occurs at the most specific step in the pathway, as that increases the fraction of epitope precursors that is not under selection pressure. While in humans it is the MHC class I molecules that are highly polymorphic and specific, other solutions do appear to exist. The TAP molecules of rats are more specific than the human TAP, and have a limited functional polymorphism, and the TAP and MHC genes of chickens are equally polymorphic on the nucleotide level 1
Chicken MHC is an interesting case, and is very strongly linked to resistance to some pathogens. But the reason for the tight linkage to resistance isn’t really known; there’s no obvious reason at the level of the MHC. It might be interesting to look at TAP as part of the resistance, as well. I have some chicken stuff in the lab, and I should see if we can test that.
- Schmid, B., Kesmir, C., & de Boer, R. (2008). The Specificity and Polymorphism of the MHC Class I Prevents the Global Adaptation of HIV-1 to the Monomorphic Proteasome and TAP PLoS ONE, 3 (10) DOI: 10.1371/journal.pone.0003525[↩][↩][↩][↩]
- Structural arrangement of the transmission interface in the antigen ABC transport complex TAP.
Oancea G, O’Mara ML, Bennett WF, Tieleman DP, Abele R, Tampé R.
Proc Natl Acad Sci U S A. 2009 Mar 18 doi: 10.1073/pnas.0811260106[↩]
Do you know if countries or regions with really fast spread/high rates of HIV infection tend to have less variation in their MHC1 pattern? Or are those about equally diverse everywhere?
The relevant question seems to be what the probability is that the virus which has evolved to seldom or never be presented on the surface of my cells will also seldom or never be presented on the surface of your cells. If that probability is much less than 1/the number of people I infect, then the virus shouldn’t become more effective at evading your immune response from evading mine. I wonder if there are places where the probability is close to, even above, 1/the number of people I infect.
Do you know if countries or regions with really fast spread/high rates of HIV infection tend to have less variation in their MHC1 pattern? Or are those about equally diverse everywhere?
If anything, the reverse; Africa tends to have more genetic diversity including MHC diversity.
There probably are places with somewhat lower MHC diversity, but it’s pretty high everywhere. The other point is that HIV seems to be very good at rapidly evolving escape mutations for almost every MHC type anyway, so it’s not an insuperable barrier.
The exception is for the handful of MHC type associated with long-term non-progressors — HLA-B51,HLA-B57, HLA-B51. To escape these MHC types is hard for the virus and it needs to develop multiple mutations to do so. So in a population with lots of one of these resistant HLA types the virus has a stronger benefit to maintaining the resistant set of mutations. (If the resistant allele is rare, then there’s little benefit to keeping the mutations.) In fact there’s some evidence that this is happening; see here for more.
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been a few years since I last worked with chickens but I thought the major difference is that the chicken only has one major expressed class I locus so it proves much easier for a virus to escape than in mammals. Interestingly the chicken TAP is also polymorphic and physically linked to the MHC so quite a different system to mammals. Jim Kaufman’s group have done quite a bit of work in this area.
Clive, you’re right that the chicken MHC is much simpler than mammalian, although at least in some strains there’s more than one MHC expressed (as isoforms, not separate genes, I believe) (I need to get this sorted out soon).
The part about variable TAP I had seen mentioned before, but I hadn’t thought through the implications.