The immune system has lots of tentacles, and viruses have to avoid all of them if they’re going to successfully infect you. Antibodies, complement, cytotoxic T lymphocytes, innate factors, interferons, interleukins, tumor necrosis factor, toll-like receptors, natural killers cells … it’s a harsh world in there for a virus, but they’re up to the task. We still have lots to learn1 about how they do it.

In the last month or so there have been three nice papers talking about viral immune evasion of natural killer cells:

MCMV m157

Structural elucidation of the m157 mouse cytomegalovirus ligand for Ly49 natural killer cell

Erin J. Adams, Z. Sean Juo, Rayna Takaki Venook, Martin J. Boulanger, Hisashi Arase, Lewis L. Lanier, and K. Christopher Garcia

PNAS 104;10128-10133 (2007)

Zoonotic orthopoxviruses encode a high-affinity antagonist of NKG2D

Jessica A. Campbell, David S. Trossman, Wayne M. Yokoyama, and Leonidas N. Carayannopoulos

J Exp Med 204:1311–1317 (2007)

Cytomegalovirus Evasion of Innate Immunity by Subversion of the NKR-P1B:Clr-b Missing-Self Axis

Sebastian Voigt, Aruz Mesci, Jakob Ettinger, Jason H. Fine, Peter Chen, Wayne Chou, and James R. Carlyle

Immunity 26:1–11 (2007)

(The figure on the left is the mouse cytomegalovirus immune evasion protein m157, from the pdb file from the Adams et al. paper. You can see the family relationship to class I major histocompatibility complexes.)

Immune evasion references

Before I talk about any of the papers, though, I want to say how cool it is to have multiple NK immune evasion papers all coming out around the same time. Our understanding of NK immune evasion has lagged well behind the T cell side (the figure on the right shows the cumulative number of papers2 of NK vs. cytotoxic T cell immune evasion. You can see how T cell research is maybe 5 years ahead of NK, which have really nothing earlier than 1993.3

Of course, the reason is that research generally works best when you’re looking under the streetlamps. Until we had some idea about how NK cells recognize their targets, it was pretty tough to figure out how viruses could block that unknown pathway. For cytotoxic T cells, the recognition mechanism (MHC class I) was reasonably well worked out by the early 1990s, and it wasn’t long after that that the explosion in research on immune evasion of that pathway followed.4 But Klaus Karre didn’t propose the “missing self” hypothesis until around 19905, and the activating receptors for NK cells weren’t at all well understood until well the mid-1990s.

The NK immune evasion findings have pretty much paralleled the state of NK cell research. The first specific NK evasion protein to be identified (that I’m aware of) was the UL18 protein from human cytomegalovirus, in 1997 or so.6 It’s an MHC class I homologue encoded by the viral genome, and after the missing-self hypothesis was widely accepted a fairly obvious question was whether UL18 could replace the self that was missing.7 Early answers were confusing, probably because of incomplete understanding of the NK recognition system, but quite recently a fairly confident and mostly positive answer8 appeared. Shortly afterward, as the understanding of NK recognition progressed to finding the activating receptors, other systems of immune evasion popped up, at first mostly relatively generic9 and then progressing to more and more specific and precise targeting, as the tools to specifically measure the individual NK cell ligands became available10.

It’s not just NK cells, of course. As we11 begin to understand toll-like receptors, for example, we’ll start to find viral interference with them. As we identify small interfering RNAs that are involved in immunity, we’ll start to find viral immune evasion mechanisms for them (of course, in plants, where the understanding of small interfering RNAs is much more advanced, viruses that block small interfering RNAs are well known). As as we find … whatever field comes up next in immunity to viruses … we’ll surely find that the viruses themselves got there a hundred million years ago, and have already stamped down the grass and settled in for a comfortable nap.

A long shot, but interesting, approach might be a reverse immune evasion approach. Find some mystery gene in a virus (there’s no shortage of mysteries); find out what it targets; and work under the assumption that it’s part of the immune system. You’d get lots of misses, but the nice thing would be that even the misses would be interesting. As a fishing expedition, though, it would be hard to fund nowadays.

  1. “The stupidest virus is smarter than the smartest virologist” — Matthias Reddehaase; quoting someone else whose name I didn’t catch[]
  2. Found on a quick and simple-minded PubMed search; I’m not claiming this is all-inclusive[]
  3. A paper by me, during my PhD! Was I really the first person, by 4 years, to mention viral immune evasion of NK cells?[]
  4. And even well before that, in the mid-19080s, the broad strokes and molecules involved were understood, so that the interactions between adenovirus proteins and MHC class I could (with some difficulty) be put into the correct context.[]
  5. I think the article was Immunol Today. 1990 Jul;11(7):237-44, but I may have missed an earlier version of the hypothesis[]
  6. Reyburn, H.T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514−517 (1997) []
  7. In case you’re not familiar with the missing self hypothesis — the concept is that natural killer cells survey potential target cells for evidence that they are “self”, meaning that they have the correct allele of MHC class I on their surface. If they do have the right MHC, the NK cell is inhibited. If not — if the cell comes from another individual and has the wrong MHC alleles, or if a virus has infected the cells and caused it to down-regulate its MHC through the viral immune evasion of T cell recognition — then the NK cell will destroy the target. []
  8. The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells. J Immunol. 2007 Apr 1;178(7):4473-81[]
  9. For example, interference with LFA-3 ( J. Immunol. 161, 2365−2374 (1998) []
  10. Such as Lodoen et al., The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions. J Exp Med. 2004 Oct 18;200(8):1075-8[]
  11. Where I say “we”, by the way, I mean scientists as a group, not me and my tapeworm[]