HCMV from J Virol
Human cytomegalovirus-infected cell

A number of viruses, especially herpesviruses, block the MHC class I antigen presentation system. It’s been widely assumed that this is for the obvious reason and that it allows the virus to avoid T cell recognition and elimination. But there’s been an awkward lack of experimental support for that assumption, to the point that I’ve begun to question it (and, more productively, to develop experimental systems with which to test it).   (See the list of posts below for some of my earlier comment on the subject.)

Now, at last, Klaus Fruh offers actual evidence that this assumption may be correct. 1

This deserves a long post, which it’s not going to get today.2 Briefly, Klaus’s group used a herpesvirus of monkeys (rhesus cytomegalovirus; rhCMV) to test this. This is closely related to the human herpesvirus human cytomegalovirus, which is a ubiquitous virus; the vast majority of humans have it, are infected with it as toddlers, remain infected with it throughout their lives, and don’t suffer any problems with it. It’s a rare cause of a mono-like disease, and it’s a concern in immune-suppressed people (especially transplant recipients), but mainly it seems to be a pretty innocuous hitchhiker.

Previous posts on MHC class I immune evasion

Immune evasion does work
Herpesvirus immune evasion: An emerging theme?

Immune evasion: Who needs it?

Viral T cell evasion in vivo: The vanishing evidence

Immune evasion: What is it good for?

The CMV family of herpesviruses carry a particularly impressive arsenal of anti-MHC class I immune evasion genes. (MHC class I is the target that antiviral T cells, also known as cytotoxic T lymphocytes or CTL, recognize. There’s an outline of the process that permits that recognition here.) Whereas herpesviruses like herpes simplex, or chicken-pox virus, and so on, seem to use only one gene to block MHC class I, CMVs seem to use three or four. This would suggest that this sort of immune evasion is really important for these viruses, but when Ann Hill actually tested that notion in mice3 removing these immune evasion genes had only a very small impact.

Fruh’s group has now done something similar using his rhesus model, and looked at an unusual characteristic of CMVs: They are able to repeatedly superinfect the same host. That is, someone4 can be infected with CMV, can have an apparently effective immune response to CMV, and yet can be infected by a new CMV virus. This is pretty unusual, of course. You’d expect that there would be a vaccine-type effect, in which the natural infection would drive a protective immune response. As far as I know, you don’t often see this sort of superinfection even with other herpesviruses, which is why, for example, the chicken-pox vaccine works.

Virus-Cell Interaction; Joerg Schroeer; Art of Science
“Human cytomegalovirus infected human endothelial cells”
by Joerg Schroeer

They made a pretty drastic mutant of the RhCMV to eliminate all four of the MHC class I immune evasion genes (taking out another half-dozen genes as collateral damage, but they checked that these weren’t confounding the story). This mutant virus, in spite of having completely lost its ability to block MHC class I, was perfectly able to infect monkeys and to set up a long-term infection — just like Ann Hill’s findings with mouse CMV. What the mutant virus was not able to do was superinfection.

Together, our results suggested that RhCMV was unable to superinfect in the absence of the homologs of US2, US3, US6, and US11 because the virus was no longer able to avoid elimination by CTL. 5

But when the pre-infected monkeys had their CTL temporarily eliminated, then the mutant viruses were able to superinfect. What’s more, after the virus got in and set up its new infection, CTL couldn’t clear them, even though the viruses still had no ability to evade MHC class I:

Our data imply that T cell evasion is not required for establishment of primary CMV infection or once the sites of persistence (e.g., kidney and salivary gland epithelial cells) have been occupied, but rather it is essential to enable CMV to reach these sites of persistence from the peripheral site of inoculation in the CMV-immune host. 5

This is really cool stuff. It offers an explanation for why Hill’s group didn’t see an effect for MHC class I immune evasion in their mouse CMV model — they didn’t specifically look at superinfection, though they looked at many other aspects of infection. (Does mouse CMV superinfect as robustly as human?)  It also offers an explanation for why experimental CMV vaccines have been ineffective — the immune evasion functions allow the virus to temporarily evade the immune response.

As I say, I don’t think superinfection is so common in other families of herpesviruses, so this may not be a universal explanation for MHC class I immune evasion by herpesviruses; but then, it’s been the CMV system that’s been most puzzling, anyway, so we may not need to go so far to look for answers after all.

  1. Hansen, S., Powers, C., Richards, R., Ventura, A., Ford, J., Siess, D., Axthelm, M., Nelson, J., Jarvis, M., Picker, L., & Fruh, K. (2010). Evasion of CD8+ T Cells Is Critical for Superinfection by Cytomegalovirus Science, 328 (5974), 102-106 DOI: 10.1126/science.1185350[]
  2. I’m still chilling with my kids on their spring break, not to mention a dozen other distractions[]
  3. Gold, M. C., Munks, M. W., Wagner, M., McMahon, C. W., Kelly, A., Kavanagh, D. G., Slifka, M. K., Koszinowski, U. H., Raulet, D. H., and Hill, A. B. (2004). Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. J Immunol 172, 6944-6953.

    Pinto, A. K., and Hill, A. B. (2005). Viral interference with antigen presentation to CD8+ T cells: lessons from cytomegalovirus. Viral Immunol 18, 434-444.

    Lu, X., Pinto, A. K., Kelly, A. M., Cho, K. S., and Hill, A. B. (2006). Murine cytomegalovirus interference with antigen presentation contributes to the inability of CD8 T cells to control virus in the salivary gland. J Virol 80, 4200-4202.[]

  4. Or some monkey[]
  5. Hansen, S., Powers, C., Richards, R., Ventura, A., Ford, J., Siess, D., Axthelm, M., Nelson, J., Jarvis, M., Picker, L., & Fruh, K. (2010). Evasion of CD8+ T Cells Is Critical for Superinfection by Cytomegalovirus Science, 328 (5974), 102-106 DOI: 10.1126/science.1185350[][]