HCV and lipid droplets, by Torsten Schaller
HCV protein associated with lipid droplets
Torsten Schaller, Research As Art)

Although there are quite a few viruses that infect and then persist in the infected animal for a long time, most of these viruses don’t cause a lot of problems during the persistent state. Herpesviruses, adenoviruses, and several other families can stick around for a long time (life-long, in the case of most herpesviruses) and although you’ll sometimes see occasional recurrence, and occasionally there can be serious disease from the reactivation (examples being shingles, from recurrent varicella-zoster virus, or the very rare cancers associated with Epstein-Barr virus) — for the most part these are really unusual outcomes. Mostly we can stroll around with our complement of viral passengers and we’re perfectly fine with it.

There are a handful of exceptions, in humans and in other animals, where viruses that cause chronic infection also cause chronic, severe disease. With these viruses we’d like to know why they become chronic in the first place (why doesn’t the immune system eliminate them?), and we’d like to know why they cause disease (why aren’t they like our friendly neighborhood herpesvirus)? We don’t have good answers for either of these questions. In fact, I don’t think we even have a good sense if the answers are the same for different viruses, or whether each of them manages to persist and cause chronic disease through their own unique factors.

Two of the most prominent chronic virus diseases in humans are HIV and HCV (hepatitis C virus). A recent paper1 suggests that these guys may have at least something in common in the way they escape immune control, and in the way the immune system controls them.

HCV protein distribution in cells
HCV protein distribution in infected hepatoma cells
(Mark Harris lab)

It’s pretty well known that one way HIV escapes immune control is that it mutates so fast, the immune system can’t get a grip on it. In particular, the cytotoxic T lymphocytes (CTL) that are specialized to control virus infections need to recognize a stretch of about 9 amino acids (a peptide, in other words), and if that sequence changes the CTL may no longer recognize the virus. (I’ve talked about that here and here.) It’s also become clear that HCV does the same thing, although perhaps less dramatically than does HIV, and that this mutational immune escape is one reason HCV can persist and continue to cause disease (see here for more).

With HIV, there are a number of “elite controllers” who seem to be resistant to the virus’s ability to mutate away from immune control. In many cases this seems to be because the CTL in those individuals are focused on a particular critical stretch of amino acids that simply can’t mutate without severely damaging the virus (reducing HIV’s replicative fitness). The reason these elite controllers select that critical peptide is that they have a MHC class I allele that specifically binds to that peptide sequence. The HLA-B27 and HLA-B57 alleles seem to be particularly likely to find critical peptides, and people with those MHC alleles are more likely to be elite controllers.

The new HCV paper1 shows that HLA-B27 is also protective against HCV infection 2, and for the same reason — the HCV peptide that binds to HLA-B27 is a critical sequence that can’t mutate much without severely damaging the virus. (When HCV does mutate away from HLA-B27-mediated control, it’s because it has developed multiple mutations in the peptide, not just one, and it’s exponentially3 harder for the virus to make two mutations vs. one.)

Is it just a coincidence that HLA-B27 is involved in both cases, or is there something specially magical about HLA-B27? I’d be inclined to say it’s just coincidence except that HLA-B27 is such a special molecule4 already. It’s involved in all kinds of disease risks, both reducing the risk of some infectious diseases like HIV and HCV and dramatically increasing the risk of autoimmune diseases like ankylosing spondylitis and many others. And off the top of my head, I think it’s one of the very ancient and highly diversified groups of HLA molecules. So maybe there is something about it that manages to focus on critical viral peptides, or that makes it a particularly strong stimulator of CTL, and that gives it a selective advantage that outweighs its increased risk of autoimmune disease.

  1. Eva Dazert, Christoph Neumann-Haefelin, Stéphane Bressanelli, Karen Fitzmaurice, Julia Kort, Jörg Timm, Susan McKiernan, Dermot Kelleher, Norbert Gruener, John E. Tavis, Hugo R. Rosen, Jaqueline Shaw, Paul Bowness, Hubert E. Blum, Paul Klenerman, Ralf Bartenschlager, Robert Thimme (2009). Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27–restricted human immune response Journal of Clinical Investigation DOI: 10.1172/JCI36587[][]
  2. This part was already known[]
  3. or maybe geometrically, I don’t know[]
  4. Unicorns have HLA-B27! Well-known fact![]