Last time I talked about immune evasion, I said how disconcerting it was to learn that immune evasion genes of mouse cytomegalovirus really don’t seem to have much of an impact on viral pathogenesis (except for the ability to infect tonsils and therefore, perhaps, spread between mice). I was equally disconcerted by a relatively old paper that I only recently found.

AdenovirusAdenoviruses are medium-sized DNA viruses that often establish long-term persistent infections.1 These persistent infections aren’t truly latent (like herpesviruses), nor are they “chronic”, like hepatitis C or HIV, which continue to replicate robustly for a long time; instead, adenoviruses seem to be able to linger around in what seems to be a low-level active infection, without doing any particular harm. As far as I know, which isn’t all that far, the mechanism by which adenoviruses are able to do this isn’t well understood. There are many different strains of adenoviruses, over 40 for humans alone, and they tend to have different lifestyles and infect different tissues in different ways. The various types of human (and some other) adenoviruses are grouped into subgroups A through F, based on sequence similarity. Research-wise, the most popular subgroup by far is Subgroup C, including types 2 and 5; these are the types that most commonly are used as vectors for vaccines and gene therapy.

The first example of viral T cell immune evasion to de described, as far as I know, was in adenovirus: 2 A glycoprotein in the E3 genomic region (“E3gp19k”) binds to MHC class I and prevents it from reaching the cell surface, thus presumably reducing the ability of CTL to recognize the infected cell. (It does other things as well, but we won’t go into that now.) About ten years ago, Linda Gooding’s lab looked at the effects of deleting this gene on mouse infection;3 their answer was that it doesn’t really do much of anything (“the E3 protein gp19K alters neither afferent nor efferent immune responses”). However, human adenoviruses don’t replicate well, if at all, in mice, so it’s not really a very good model, and so I wasn’t very distressed by that observation. I comforted myself with the knowledge that E3gp19k is quite conserved in its sequence, so that it must be strongly selected for.

E3gp19k phyloOddly, though, while E3gp19k sequences are conserved within adenovirus subgroups, between the different subgroups they’re really quite different. (Phylogenetic tree on the left shows the clustering of E3gp19k among a number of adenovirus subgroups.) So something keeps the protein sequence similar among similar viruses — it’s strongly selected — but between subgroups it can diverge quite widely. I’m not sure what that means. Presumably this reflects something about the different virus lifestyles, but I don’t know enough about the different lifestyles to make any sweeping generalizations; nor is there anything know as yet about any functional differences (if any) between the various subgroups’ E3gp19k.

In fact, some human adenovirus subgroups don’t even seem to have any E3gp19k at all. I assumed that these viruses either have a very divergent variant of E3gp19k, that I wasn’t picking up in my Blast searches, or else that they have evolved some other form of T cell immune evasion molecule. However, that assumption has been deeply shaken by the paper I mentioned:
Lack of effect of mouse adenovirus type 1 infection on cell surface expression of major histocompatibility complex class I antigens.
Kring SC, Spindler KR.
J Virol. 1996 Aug;70(8):5495-502.

Here, they’re looking at mouse adenovirus rather than human. This virus, like some of the human subgroups, apparently has no E3gp19k protein in its genome. Spindler — probably guessing, like me, that the virus must have some other protein with a similar function — put the virus through a pretty exhaustive battery of experiments, and quite conclusively show that at least in vitro the virus doesn’t do a damn thing to MHC class I. So, either the virus does something in vivo that it doesn’t do in vitro:

One model is that a unique cell type exists in which MAV-1 infection down regulates class I MHC surface expression. … While endogenous expression of MAV-1 E1A activity did not induce a decrease of class I MHC antigen levels in MAV-1-infected cells in our studies, it remains possible that we did not analyze the unique cell type in which this mechanism could operate.

Or else the virus doesn’t care about avoiding CTL, and if that’s the case, it strengthens the case against immune evasion molecules (even in viruses that express them) being all that important for pathogenesis:

An alternative model is that decreased class I MHC surface expression is not important to the ability of MAV-1 to persist and that another mechanism is active … the demonstrated ability of the E3 gp19K protein to decrease the surface expression of class I MHC antigens in vitro may not be indicative of an ability to significantly alter the cell-mediated immune response to an infection in vivo.

My bias, for a long time, has been that viruses like herpesviruses and adenoviruses must care deeply about evading CTL. I’m going to have to rethink that bias.

  1. They’re kind of like the poor man’s herpesvirus.[]
  2. An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens. Burgert HG, Kvist S. Cell. 1985 Jul;41(3):987-97.[]
  3. The role of human adenovirus early region 3 proteins (gp19K, 10.4K, 14.5K, and 14.7K) in a murine pneumonia model. Sparer TE, Tripp RA, Dillehay DL, Hermiston TW, Wold WS, Gooding LR. J Virol. 1996 Apr;70(4):2431-9.[]