Any time a species meets some kind of barrier, there’s going to be selection to overcome that barrier. In the case of pathogens, one major barrier they have to hurdle is their hosts’ immune systems. What’s more, this isn’t a simple, static barrier. Immune systems change on a day-to-day basis; and immune systems also change on a population basis, as the individuals in the host population are in turn selected by the pathogen.
Last week I talked about an example where a population — frogs in the UK, in this case — are apparently being selected by a pathogen. The relatively recent introduction of frog virus 3 into the UK has caused large-scale die-offs of frogs there, and Teacher et al. have just shown evidence that the survivors have been selected for a particular MHC class I type.
MHC class I is often associated with resistance to viruses, because it’s responsible for recognition by antiviral T cells. What probably happens is that viruses sweep through a population, infecting (and imposing a selective pressure on) most members of the population. A few individuals that happens to have some particular MHC class I type are relatively resistant to the virus, and have a selective advantage; that MHC allele becomes more frequent in the population; and the population as a whole becomes relatively resistant to the virus. Of course, this now presents a new barrier to the original virus, and there’s selective pressure on it; virus mutants that are resistant to that particular MHC type do better; the virus sweeps through the new population; and a new minority with a different MHC type has a new selective advantage.
This is the most popular model (“frequency-dependent selection”), but it’s been hard to definitively show examples of it because things are happening on a evolutionary timescale. Even with the very rapid (as evolution goes) change in the UK frogs’ MHC, we don’t have all the pieces. We see that frogs in the UK have a different set of MHC alleles than those frogs that haven’t been exposed to FV3, but we don’t have the population frequencies of these alleles over the time since the virus was introduced. And we don’t have examples of the virus accommodating itself to the new MHC; we’d see that as virus sequences changing over time.
Last week I ended the frog story by saying:
Some people may wonder if this frog virus story has any real relevance to humans. Well, apart from the pure scientific interest of tracking a potential frequency-dependent selection event in real time, one of the clearest links between an MHC class I allele and resistance to a viral infection is in humans, where the MHC class I alleles HLA-B27 and HLA-B57 are linked to resistance to HIV and HCV. Is it possible for HIV to adapt at the population level, so that the dominant strains of HIV in the world are no longer contained by HLA-B57? More generally, if we succeed in developing a T cell-based vaccine against HIV, it will probably have strong allele-dependent effects — will HIV adapt to this vaccine?
Astute readers may have guessed that I wasn’t just guessing wildly, and indeed I had already seen the paper from Kawashima et al., on exactly this topic.
Even though HIV is generally incredibly good at ripping through human immune responses without being controlled, there are some people who are long-term non-progressors (LTNP); they’re infected with HIV, yet they manage to control the virus pretty well, without antiviral treatment, for long periods. Many of these people, it turns out, have a particular subset of MHC class I types; they’re much more likely than the general population to have the HLA-B51, HLA-B57, or HLA-B27 MHC class I alleles.
HIV normally mutates very rapidly within infected individuals, so that as an antiviral immune response arises the virus may be temporarily controlled, but the new mutations that arise escape from the immune control and continue to replicate. It seems that this immune escape is less likely to happen when the individual has one of the LTNP-associated alleles, and that’s probably because the immune target associated with HLA-B51 (etc) is essential for the virus’s survival. When HIV mutates the immune target, the virus can’t replicate properly. The only way HIV can escape immune control by people with these MHC alleles is to make multiple mutations at the same time, compensating for the escape mutation with several other changes. These multiple mutations are exponentially less probable than single mutations, so the virus is essentially controlled, for a long time.
Humans are today a very large, highly mixed population, and it would take a vast plague, even worse than HIV, to rapidly cause frequency changes that we could measure in the brief period since HIV become common. But that hasn’t always been true; humans historically have included relatively small and isolated populations subject to intense disease selection, and we believe we see the outcome of that today in that different human populations have different frequencies of HLA-B51, B57, and B27 — the equivalent of frogs in the UK vs. elsewhere.
What’s happening to HIV in those areas where HLA-B51 is common? The prediction is that viruses that have managed to make the mutations that give resistance to HLA-B51 should have a selective advantage in those areas that isn’t seen elsewhere. That’s precisely what Kawashima et al. saw.
… the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level.
|HLA-B51 complexed with an immunodominant HIV peptide
Immune escape isn’t the only selective pressure on HIV. There’s the ability to spread from one individual to another, for example, which isn’t necessarily linked to immune escape. In principle, some of the other selective factors may counteract immune escape selection. And in general, some (though not all) of the mutations that allow a virus to escape immune control by on individual are harmful to the virus. That means that some of the escape sequences will quickly revert back to the generic HIV sequence. If HLA-B51 is rare in the population, the virus will constantly be reverting back to generic sequences and the HLA-B51-resistant strain will not particularly accumulate. But if HLA-B51 is common, even these reverting sequences will build up in the population.
As anticipated, non-reverting variants such as I135X accumulate at the population level, but even rapidly reverting mutations such as T242N can accumulate, if the selection rate exceeds the reversion rate
Perhaps as a result, formerly-protective MHC alleles are no longer protective in some areas:
Data here suggest that, whereas 25 years ago HLA-B*51 was protective in Japan, this is no longer the case. The apparent increase in I135X frequency in Japan over this time supports the notion that HLA-B*51 protection against HIV disease progression hinges on availability of the HLA-B*51-restricted TAFTIPSI response. However, whether this is the case remains unknown.
Any effective anti-HIV vaccine will probably rely on antiviral T cells, and will therefore rely on MHC class I presentation. What this paper suggests is that HIV is likely to be a moving target. Even if an effective vaccine is developed, it is possible that the virus will gradually evolve resistance to the vaccine.
Thus, the data presented here, showing evidence that the virus is adapting to CD8+ T-cell responses, … highlight the dynamic nature of the challenge for an HIV vaccine. … The induction of broad Gag-specific CD8+ T-cell responses may be a successful vaccine strategy, but such a vaccine will be most effective if tailored to the viral sequences prevailing, and thus may need to be modified periodically to keep pace with the evolving virus.
Since we still don’t have any vaccine that protects against HIV at all, this is pretty much a hypothetical worry. Still, it’s something to think about for the future.