I have as much respect for viruses’ ability to manipulate their host as the next guy, and I’m probably more of a fan of viral immune evasion than that next guy. But I still do think that coincidences do happen.

A paper from John Trowsdale and colleagues1 shows that Kaposi’s Sarcoma Herpesvirus (KSHV) destroys HFE, and they suggest that this is “a molecular mechanism targeted by KSHV to achieve a positive iron balance.” Without dissing their observations (which are perfectly convincing) I’m not entirely convinced by their conclusion. Still, it’s an interesting suggestion, and I’m keen to see some kind of followup to it.

The reason I’m not convinced is that this has the look of a spillover effect to me. We already know that KSHV attacks MHC class I molecules via its K3 and K5 molecules, and that it does so by targeting the cell-surface pool to lysosomes. This is a very familiar pattern; most, if not all, herpesviruses block MHC class I molecules. Although it’s been hard to formally prove “why” herpesviruses do this,2 the general assumption is that this allows the virus to at least partially avoid recognition by T cells, and this lets the virus survive better — perhaps because it builds a larger population very early, or perhaps because it is able to last longer late, or whatever.

At any rate, there’s a fairly simple and logical reason why it would make sense for KSHV to block MHC class I molecules, and as I say they do, in fact, do this. Now, why would they attack HFE? HFE is an iron-binding protein that’s involved in the regulation of iron metabolism. Why would KSHV be interested in iron metabolism?

Quite a few pathogens are actually very concerned about iron metabolism, of course. Bacteria generally need iron for their metabolism,3 and pathogenic bacteria have evolved ways of grabbing iron away from their hosts (while their hosts have evolved way of holding on tighter and tighter to that iron). But in general viruses, as opposed to bacteria, don’t have specific needs for iron. Trowsdale’s group makes the argument — and offers some experimental evidence — that KSHV does in fact want iron. “KSHV presumably down-regulates HFE to affect iron homeostasis,” they say, and “These results indicated an iron requirement for lytic KSHV and with the virus targeting HFE to satisfy this demand.” However, I don’t think they really show this directly; they show that there are changes in iron receptors in the presence of KSHV, but as far as I can see they don’t show that the presence or absence of iron actually affects the virus in any way.

HFE complex HLA-A2 complex
HFE heavy chain (red) complexed with beta-2 microblogulin (blue) HLA-A2 (classical MHC class I) heavy chain (red) complexed with beta-2 microblogulin (blue) and a peptide (green)

So let’s say KSHV doesn’t really care about iron per se. Why is the virus attacking this iron receptor, then? To me, the simpler solution is that it’s just a side effect of the virus attack on MHC class I, because HFE is in fact an MHC class I molecule.4 Not all MHC class I molecules are involved in immunity, and HFE is the classic counterexample, an MHC class I molecule that has a clear non-immune role. 5

Even though HFE has a different role, it has a very similar structure to the classical MHC class I molecules — see the images to the right (click for larger versions), and for more comparisons see my post from a couple of years ago, “MHC Molecules: The Sitcom“.  It doesn’t have the peptide bound in the top groove (green in the HLA-A2 complex here) that classical MHC class I molecules use to provide specific signals to T cells, but it’s very similar. It’s plausible — at least to me — that the virus doesn’t care in the least about iron metabolism, but is just attacking everything on the cell surface that looks like an MHC class I molecule, and HFE is getting caught in the covering fire.

Interestingly, though, this isn’t the first time this has been proposed.  A few years ago a paper from Drakesmith et al proposed pretty much the same model for HIV, via the HIV immune evasion molecule nef.  Nef downregulates a large number of immune-related molecules, and also downregulates HFE. Drakesmith et al, like Trowsdale’s group, argue that this is “deliberate”, and that the modified iron metabolism directly benefits HIV;6 but I don’t know if that’s been followed up (Trowsdale’s paper, surprisingly, doesn’t cite Drakesmith et al).

I’m open to the idea that viruses do “want” to tweak iron metabolism, because that would be pretty cool, but so far I’m leaning to notion that HFE is just an accidental victim of the viral war on immunity.

  1. Rhodes DA, Boyle LH, Boname JM, Lehner PJ, & Trowsdale J (2010). Ubiquitination of lysine-331 by Kaposi’s sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation. Proceedings of the National Academy of Sciences of the United States of America PMID: 20805500[↩]
  2. I put “why” in quotes because obviously it’s not planned. But it’s easier than saying, “why herpesviruses have evolved this ability” or “what selective advantage this ability confers to the herpesviruses”.[↩]
  3. I say “generally” because I’m not a bacteriologist, and no doubt there’s some bizarre oddball bug that doesn’t need iron to get along. But I don’t know any of them. As far as I know bacteria all need iron[↩]
  4. It’s a class Ib molecule, a non-classical MHC class I molecule, but it is MHC class I.[↩]
  5. It’s worth noting that HFE might — just might — have an immune role, too. There are T cells that recognize HFE. It’s not clear, at least to me, what these T cells do, and whether they have a real function or if it’s just a case –another case? — of accidental spillover.
    Rohrlich PS, Fazilleau N, Ginhoux F, Firat H, Michel F, Cochet M, Laham N, Roth MP, Pascolo S, Nato F, Coppin H, Charneau P, Danos O, Acuto O, Ehrlich R, Kanellopoulos J, & Lemonnier FA (2005). Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proceedings of the National Academy of Sciences of the United States of America, 102 (36), 12855-60 PMID: 16123136[↩]
  6. Drakesmith H, Chen N, Ledermann H, Screaton G, Townsend A, & Xu XN (2005). HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 102 (31), 11017-22 PMID: 16043695[↩]