Human papillomavirus capsidTwo themes I’ve repeatedly raised in this blog are viral immune evasion, and tumor immune evasion. There are similarities between them (both viruses and tumors are attacked by the same components of the immune system) and differences (a virus species comes from a common ancestor, so each member of the virus species will use the same mechanism; while tumors all arise de novo, and no matter how similar they appear clinically or histologically they have had to discover their own pathway to immune evasion).

The differences become less obvious when we talk about virus-induced tumors, and especially when it turns out that part of the viral tumorigenesis process includes immune evasion.

Most of the viruses that are good at MHC class I immune evasion are relatively large: Herpesviruses, poxviruses, even adenoviruses and retroviruses have reasonably good-sized genomes (as viruses go, which isn’t very far). Smaller viruses still have immune evasion functions, but they tend to focus more on cytokines, like interferons. This is only a rule of thumb, though, and there are a number of papers over the past years pointing at immune evasion of MHC class I by fairly small viruses. In particular, papillomaviruses (which are fairly small viruses — only about 8000 base pairs in their genome, and maybe 7 or 8 proteins) have  been implicated in this.

As far as I know the original observation was in 2002;1 the original obervation, with bovine papillomavirus, was followed and extended (mostly by the same group, Campo’s) with evidence that the viral protein E5 binds to MHC class I and prevents its expression. 2

Papillomavirus replication
Papillomavirus genome (red) and E4 protein (green);
nuclei in blue. From ref. 3

Papillomaviruses are tumor viruses, and the high-risk papillomaviruses are responsible for most cases of cervical carcinoma. The virus proteins involved in the tumorigenesis are E6, E7, and (you guessed it) E5. This at first glance seems to suggest that E5 might contribute to tumor progression by blocking antigen presentation — and that may well be the case; but the problem is that E5 often isn’t present by the time tumors are clinically relevant. That is, you need E6 and E7 in a papillomavirus-caused cancer, but while E5 may help it get going it’s not necessary for continued cancer development.

That becomes  easier to understand when we take into account a series of papers that showed that high-risk papillomaviruses attack MHC class I with their E7 protein as well. 4 The E7 protein apparently regulates MHC expression at the RNA level, so that MHC class I (and other components of the pathway) are not synthesized at all. (This is also what’s seen with some ‘tumorigenic’ adenoviruses, which don’t have the E3 protein that ‘normal’ adenoviruses use to downregulate MHC class I.)

Both of these proteins, E5 and E7, immune evasion functions are probably ‘designed’  for immune evasion in a natural virus infection — cancers are by no means a normal outcome for papillomaviruses, and even for high-risk papillomaviruses cancers are a rare, aberrant, and probably dead-end outcome. Even though the cancers are abnormal, though, they probably benefit from the immune evasion the virus uses normally.

I don’t know how much of this has been tested, but I speculate that the E5 probably helps early on in tumor development — letting the tumor progress a little further while sheltered from the immune system. I’m a little dubious how completely MHC class I can be turned off by transcription factors like E7, and I suspect that there would be a quite a bit of residual MHC class I left over, that E5 could then soak up. Perhaps later in tumor development, then, as the tumor has undergone repeated mutagenesis and selection by the immune system, E5 is no longer necessary and can be lost with impunity.

  1. Down-regulation of MHC class I by bovine papillomavirus E5 oncoproteins. Ashrafi GH, Tsirimonaki E, Marchetti B, O’Brien PM, Sibbet GJ, Andrew L, Campo MS. Oncogene. 2002 Jan 10;21(2):248-59. []
  2. E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain. Ashrafi GH, Haghshenas M, Marchetti B, Campo MS. Int J Cancer. 2006 Nov 1;119(9):2105-12.
    Ashrafi GH, Brown DR, Fife KH, Campo MS. Down-regulation of MHC class I is a property common to papillomavirus E5 proteins. Virus Res. 2006 Sep;120(1-2):208-11. []
  3. Doorbar, Clinical Science (2006) 110, (525–541) []
  4. Georgopoulos NT, Proffitt JL, Blair GE. (2000). Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins. Oncogene 19: 4930-4935.
    Li H, Ou X, Xiong J, Wang T. (2006). HPV16E7 mediates HADC chromatin repression and downregulation of MHC class I genes in HPV16 tumorigenic cells through interaction with an MHC class I promoter. Biochem Biophys Res Comm 349: 1315-1321[]