MHV68 (Stevenson)
MHV–68 exiting an infected cell (Stevenson lab)

Some viruses burn through their hosts like a flamethrower, blasting past defenses for a brief shining moment and then hurtling on through the next victim. Other viruses slip in, delicately negotiate an understanding with the immune system, and set up a long-term relationship with the host. Herpesviruses do the latter, and to me, at least, they’re more interesting than their less restrained cousins.

Herpesviruses set up long-term, usually lifelong, latent infections in their hosts. The cells that harbor the latent infections depend on the precise virus; gamma-herpesviruses like Epstein-Barr virus (EBV) typically go latent in lymphocytes. EBV only infects humans, so it’s kind of hard to do actual experiments (as opposed to observational studies) but a possible model for EBV is a mouse gamma-herpesvirus, mouse herpesvirus 68 (MHV68). I’ve talked about this virus before here, in the context of immune evasion; MHV68 has a gene that apparently allows it to avoid T cell recognition in the initial stages of infection, and this immune evasion in the early stages of infection helps determine the extent, and stability, of the latent phase. In the latent phase, though, the immune evasion molecule might not be all that helpful. What regulates the numbers of persistently-infected lymphocytes?

Immunodominance is another theme I’ve talked about several times here. Immunodominance is the phenomenon in which T cells focus their response on a small number of potential targets. A typical virus — especially a large virus, like a herpesvirus — might have hundreds or thousands of potential T cell targets (“epitopes”), according to the simpler prediction programs; but in practice, only a tiny handful of those hypothetical epitopes are actually recognized efficiently by T cells in the host. The molecular mechanisms that determine immunodominance aren’t well understood, and in many cases the importance of immunodominance isn’t clear, either. In the case of HIV, and perhaps a couple of other viruses, there’s evidence that immunodominance affects the course of infection, but there aren’t many such clear examples.

MHV68 is apparently another example. A paper from Marques et al.1 shows that in one particular mouse strain, T cell recognition of a single epitope of MHV68 is critical in determining how much latent virus hangs about in the infected mouse. Mutating that single epitope (so that it was no longer recognized by T cells) cranked up the level of latent infection dramatically.

MHV68-infected lung
Lung section from a MHV68–infected mouse

In this case, the immunodominance is not so mysterious; there aren’t all that many genes expressed during latency (pretty much by definition) and so there aren’t many possible sources for the dominant epitope. Still, it’s surprising (to me) that a single epitope can have such a dramatic effect on the pathogenesis of the virus; I can’t think of very many instances of that. An obvious question is whether this is unique to this particular mouse strain (because mouse strains typically see different epitopes) or whether this is a general phenomenon. That’s a really hard question to answer, but the authors point at a little bit of circumstantial evidence: Apparently the gene that’s the source of the epitope shows evidence that it’s under more selection than are the neighboring genes.

So the authors’ model for this virus’s pathogenesis, as I understand it, would be something like this: In the initial infection, the virus expresses many genes, and probably has many targets for the immune system. But some of the genes it expresses are immune evasion genes, which dampen but don’t eliminate the immune response, allowing the virus to get access to the lymphocytes it needs for latent infection. The virus constantly, though slowly, reactivates, so that there should be fewer latently-infected lymphocytes over time; that’s counteracted by the virus forcing the lymphocytes to replicate themselves at about the same rate. At the same time, though, latently-infected lymphocytes will be also gradually depleted by the immune system. This immune-mediated depletion depends on the virus having a target for the T cells to see; because there are only a small number of latently-expressed genes, there are only a few possible targets for the T cells. Immunodominance (probably) narrows this even more, in this case to a single T cell epitope. Get rid of that epitope and there’s no target at all, so that instead of merely keeping pace with the depletion, the virus can at least temporarily get ahead of the depletion, increasing the latent set-point of the virus.

In the case of EBV, at least, it’s likely that the latent set-point is important in disease, so (if MHV68 really is a model for EBV infection, which is a little controversial) this may be an example of immunodominance determining disease.


  1. Sofia Marques, Marta Alenquer, Philip G. Stevenson, J. Pedro Simas, Ann B. Hill (2008). A Single CD8+ T Cell Epitope Sets the Long-Term Latent Load of a Murid Herpesvirus PLoS Pathogens, 4 (10) DOI: 10.1371/journal.ppat.1000177[]