MycobacteriaCD1 is a fascinating molecule, but it hasn’t traditionally been associated with antiviral protection. Viruses, however, seem to disagree.

CD1 is (actually, CD1 are, since these are a family of related molecules) members of the MHC class I family, with many of the traditional MHC class I features — binding to β2-microglobulin, a “groove” made of two alpha-helices on top of a beta-pleated sheet ( (in classical MHC, the peptide-binding groove: the “bun” of the peptide’s “hot dog”).

I previously wrote a field guide to the MHC family that shows these features across a wide range of the MHC family, but here are some comparisons of CD1d (PDB number 2GAZ) to classical MHC (HLA-A2; PDB number 2GTW). Here I’m showing the “heavy chain” of the complex in red, the ligand that fits in the binding groove is green, and β2-microglobulin in blue. (The “top view” is looking “down” at the molecule more or less as a T cell would “see” it; the ribbon view lets you see the ligand interactions a little more easily; the “ligand only” view shows the thing that goes in the groove with all the MHC or CD1 resides removed.) (Click on a molecule for a larger version.)

Side view Top view Top view (ribbon) Ligand only
CD1d CD1d, side view CD1d, top view CD1d, top view CD1d ligand
HLA-A2 HLA-A2, side view HLA-A2, top view HLA-A2, top view HLA-A2 ligand

The similarities are pretty obvious, but it’s the difference that makes CD1 particularly interesting. Classical MHC molecules present peptide ligands; CD1d presents, instead, very hydrophobic molecules: lipids, glycolipids, and lipopeptides. These sorts of things are typically found in mycobacteria (as with phosphatidylinositol mannoside, shown in the images here), and I’ve thought of CD1 as an example of how our physiology has been shaped by pathogens — this whole branch of the immune system, devoted to detection and elimination of tuberculosis and leprosy.

My view started to slip in around 2000, with Frank Chisari’s observation that NKT cells may be involved in control of hepatitis B virus in his transgenic mouse model.1 (NKT cells are the main lymphocytes that recognize CD1 molecules.) I’ve talked about Chiasri’s HBV mouse model before — it’s so artificial that I always am hesitant to extrapolate from it. That said, his findings in that model have all (as far as I know) held up in more natural systems, and the NKT observation is no exception; several other groups have seen similar things. 2

Raftery et al., 2008 Fig. 10What really confirmed to me that CD1 can be antiviral, though, was the virus’s side of the story. Viruses employ an arsenal of anti-immune molecules, presumably targeting whichever immune components that are especially dangerous to the particular virus. Over the past few years, there’s been an increasing number of sightings of viruses that block CD1-mediated presentation. The first (that I know of) was HIV,3 and since then vaccinia virus4 and herpes simplex5 have also been shown to block CD1-mediated antigen presentation. The latest addition to the list is human cytomegalovirus.6 These viruses (HIV, poxviruses, and herpesviruses) are particularly good at blocking classical MHC class I presentation as well; I don’t know if this dual blockade is typical, or if people have mainly looked in those viruses most renowned for immune evasion — in other words, maybe we’re seeing this double action because people are looking under the streetlamps.

It’s interesting that HSV and HCMV (though not HIV, which blocks both classical MHC class I and CD1 with the same protein, nef) have apparently developed separate systems to block CD1 and classical MHC. The molecules responsible for their CD1 blockade are not yet identified, but they don’t seem to be the same as the ones that block MHC class I. If CD1 blockade is the main function of these genes (and not a side-effect of blocking some other aspect of immunity, say), the implication is that CD1 is an important-enough player in controlling these viruses that they have had to maintain distinct pathways to escape from it.

I wonder what it’s doing.

  1. Kakimi, K., Guidotti, L. G., Koezuka, Y., and Chisari, F. V. (2000). Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192, 921-930.[]
  2. For example, Grubor-Bauk, B., Simmons, A., Mayrhofer, G., and Speck, P. G. (2003). Impaired clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant V alpha 14-J alpha 281 TCR. J Immunol 170, 1430-1434. []
  3. Shinya, E., Owaki, A., Shimizu, M., Takeuchi, J., Kawashima, T., Hidaka, C., Satomi, M., Watari, E., Sugita, M., and Takahashi, H. (2004). Endogenously expressed HIV-1 nef down-regulates antigen-presenting molecules, not only class I MHC but also CD1a, in immature dendritic cells. Virology 326, 79-89.[]
  4. Webb, T. J., Litavecz, R. A., Khan, M. A., Du, W., Gervay-Hague, J., Renukaradhya, G. J., and Brutkiewicz, R. R. (2006). Inhibition of CD1d1-mediated antigen presentation by the vaccinia virus B1R and H5R molecules. Eur J Immunol 36, 2595-2600.[]
  5. Sanchez, D. J., Gumperz, J. E., and Ganem, D. (2005). Regulation of CD1d expression and function by a herpesvirus infection. J Clin Invest 115, 1369-1378.
    Yuan, W., Dasgupta, A., and Cresswell, P. (2006). Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling. Nat Immunol 7, 835-842.[]
  6. Raftery, M.J., Hitzler, M., Winau, F., Giese, T., Plachter, B., Kaufmann, S.H., Schonrich, G. (2008). Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus. Journal of Virology, 82(9), 4308-4319. DOI: 10.1128/JVI.01447-07[]