Meggan Gould, Crow 104
“Crow 104” by Meggan Gould

The other day I heard a fascinating talk from Ned Walker, on the ecology and evolution of West Nile Virus in birds and mosquitos. Hopefully some of Ned’s cooler stuff should be published relatively soon, and I’ll talk about it then. In the mean time, Ned’s seminar reminded me of a really baffling observation I remembered reading about, in the mid 1990s, and prompted me to see what had happened to that story. As far as I can find, at present the state of the art regarding it seems to be (A) a big shrug, and (B) the suggestion that it’s an irrelevant side effect — the sort of thing that should make Larry Moran happy.

West Nile Virus (WNV) is a member of the flavivirus family, which are small (~11,000 bases) single-stranded RNA viruses that typically infect many species and often have an insect vector. For unknown reasons, in the mid 1990s WNV started to spread out of its traditional geographical regions (which are, you’ll never guess, the western Nile region of Africa) through much of Africa and Europe, and then hopped into North America and now has spread across the continent. It’s dangerous to humans (4269 cases, 177 fatalities in the USA in 2006) and much worse to birds — causing local extinctions of some species,1 especially crows2 (which, by the way, Ned3 thinks have got a bad rap as carriers — he thinks crows may be dead-end species, while many other species may be the actual routes of transmission).

Anyway, all this flavivirus talk reminded me of this previous observation.4 The reason I remember it was that it came out when I was particularly obsessed (even more so than I am today, believe it or not) with viral immune evasion; and the paper described exactly the opposite effect of what I was expecting.

Class I major histocompatibility complexes are recognized by cytotoxic T lymphocytes, which are generally agreed to be a major antiviral force; as such, many viruses target MHC class I and thereby block CTL recognition. 5 So it’s pretty common for virus-infected cells to show reduced levels of MHC class I.

West Nile Virus, transmission EM, from Wellcome Images
West Nile Virus

Mullbacher’s paper showed that flaviviruses do the opposite: They specifically up-regulate surface levels of MHC class I. (As it happens, this had been described earlier, though I think only in specific cell types,6 but this was the first time I had run into it.) Mullbacher’s group argued, and still argues, that this is because the virus specifically increases peptide transport into the endoplasmic reticulum (in the 1995 paper, they guessed that a general leakiness might be the cause; later, they argue that it’s a specific effect on the TAP peptide transporter.7 ) Other groups believe that it’s a transcriptional effect, through several different (interferon-dependent and -independent) pathways.8 Still, the phenomenon seems real, significant, and robust.

How come? What’s the benefit to the virus to up-regulate MHC class I, thus making itself a better target to CTL?

Over the years (I found out, once I picked up on this story again last week) a bunch of different explanations have been proposed — resistance to natural killer cells, and so on; but none of them have been very convincing, and more recently, you get the sense that the researchers are just growing tired of it. (“MHC class I up-regulation by flaviviruses: Immune interaction with unknown advantage to host or pathogen.”9)

The latest article on the subject I’ve been able to find10 argues that it’s just a side-effect of the flavivirus life-cycle, and has nothing to do with immunity one way or another:

We propose that the phenomenon of flavivirus-mediated MHC class I upregulation is a by-product of a unique assembly strategy evolved by flaviviruses and therefore did not evolve primarily as an immune escape mechanism for virus growth in the vertebrate host.

Correct or not, it’s a reasonable suggestion, and a useful reminder that not everything we can measure is adaptive. However, if the other groups’ transcriptional arguments are correct, then the phenomenon sounds more like the infected cells’ attempt at host defense — which I would file under the “adaptive” category, even if it’s not actually effective in this case.

  1. LaDeau, S. L., Kilpatrick, A. M., and Marra, P. P. (2007). West Nile virus emergence and large-scale declines of North American bird populations. Nature 447, 710-713. []
  2. The photo at the top, by the way, is by Meggan Gould[]
  3. I see that other groups have reached a similar conclusion, especially implicating robins as important transmission species[]
  4. Mullbacher, A., and Lobigs, M. (1995). Up-regulation of MHC class I by flavivirus-induced peptide translocation into the endoplasmic reticulum. Immunity 3, 207-214.[]
  5. At least, that’s the accepted wisdom — but see my previous discussions of that.[]
  6. King, N. J., Maxwell, L. E., and Kesson, A. M. (1989). Induction of class I major histocompatibility complex antigen expression by West Nile virus on gamma interferon-refractory early murine trophoblast cells. Proc Natl Acad Sci U S A 86, 911-915.[]
  7. Momburg, F., Mullbacher, A., and Lobigs, M. (2001). Modulation of transporter associated with antigen processing (TAP)-mediated peptide import into the endoplasmic reticulum by flavivirus infection. J Virol 75, 5663-5671.[]
  8. For example, Cheng, Y., King, N. J., and Kesson, A. M. (2004). Major histocompatibility complex class I (MHC-I) induction by West Nile virus: involvement of 2 signaling pathways in MHC-I up-regulation. J Infect Dis 189, 658-668.[]
  9. Lobigs, M., Mullbacher, A., and Regner, M. (2003). MHC class I up-regulation by flaviviruses: Immune interaction with unknown advantage to host or pathogen. Immunol Cell Biol 81, 217-223.[]
  10. Lobigs, M., Mullbacher, A., and Lee, E. (2004). Evidence that a mechanism for efficient flavivirus budding upregulates MHC class I. Immunol Cell Biol 82, 184-188. []