It’s never been very clear to me why a virus would want to invest in blocking MHC class II. Since there are viruses that apparently do invest this way2 I may be missing something about virus-host interactions.
MHC class II is certainly critical to the immune response. People without MHC class II, as in some forms of “bare lymphocyte syndrome”, have severe immunodeficiency; unless they receive bone marrow transplants they usually die as children, of overwhelming viral, bacterial, and fungal infections. That’s because MHC class II is recognized by T helper (CD4) T cells, which are the foundation of most adaptive immune responses. It’s easy to imagine how targeting MHC class II could benefit a pathogen.
So why am I puzzled by viruses that target MHC class II? The thing is that viruses are intracellular parasites, whereas MHC class II mainly presents peptides from extracellular sources. A virus may be able to block MHC class II presentation on the cell it’s infecting, but so what? It’s the neighbouring, uninfected cell that will present the virus peptides to CD4 cells and get the immune response moving.
(By contrast, of course, it’s obvious in principle how blocking MHC class I would benefit a virus. MHC class I molecules present peptide from intracellular molecules, so a virus can block the same molecules that will cause the immune response.)
The particular paper that reminded me that this bugs me, by the way, is:Hussain, A., Wesley, C., Khalid, M., Chaudhry, A., Jameel, S. (2007). Human Immunodeficiency Virus Type 1 Vpu Protein Interacts with CD74 and Modulates Major Histocompatibility Complex Class II Presentation. Journal of Virology, 82(2), 893-902. DOI: 10.1128/JVI.01373-07
They show that the HIV Vpu protein binds to invariant chain, a binding partner of MHC class II that (among other things) helps MHC class II traffic to the proper endosomal compartment. I didn’t peer-review this paper: I would have asked for several more experiments. Still, overall the actual association between Vpu and invariant chain looks fairly convincing, and there does seem to be an effect (though not a terribly impressive one) on overall MHC class II surface expression and on antigen presentation.
This is not the first time a viral protein has been shown to affect MHC class II. The human cytomegalovirus proteins US23 and US34 both affect MHC class II as well as MHC class I; herpes simplex virus is supposed to attack several steps in MHC class II antigen processing,5 again as well as MHC class I; and there are a handful of other examples. Aside from the HCMV US2 story, few have been studied in any detail, as far as I know, and in no case is their role in pathogenesis known.
HIV budding from a lymphocyte
So how might it make sense for a virus to block MHC class II antigen presentation? There are some ways in which this would make sense, but I don’t think any of them are particularly good answers.
MHC class II is certainly critical to the immune response. People without MHC class II, as in some forms of “bare lymphocyte syndrome”, have severe immunodeficiency; unless they receive bone marrow transplants they usually die as children, of overwhelming viral, bacterial, and fungal infections. That’s because MHC class II is recognized by T helper (CD4) T cells, which are the foundation of most adaptive immune responses. It’s easy to imagine how targeting MHC class II could benefit a pathogen.
So why am I puzzled by viruses that target MHC class II? The thing is that viruses are intracellular parasites, whereas MHC class II mainly presents peptides from extracellular sources. A virus may be able to block MHC class II presentation on the cell it’s infecting, but so what? It’s the neighbouring, uninfected cell that will present the virus peptides to CD4 cells and get the immune response moving.
(By contrast, of course, it’s obvious in principle how blocking MHC class I would benefit a virus. MHC class I molecules present peptide from intracellular molecules, so a virus can block the same molecules that will cause the immune response.)
The particular paper that reminded me that this bugs me, by the way, is:Hussain, A., Wesley, C., Khalid, M., Chaudhry, A., Jameel, S. (2007). Human Immunodeficiency Virus Type 1 Vpu Protein Interacts with CD74 and Modulates Major Histocompatibility Complex Class II Presentation. Journal of Virology, 82(2), 893-902. DOI: 10.1128/JVI.01373-07
They show that the HIV Vpu protein binds to invariant chain, a binding partner of MHC class II that (among other things) helps MHC class II traffic to the proper endosomal compartment. I didn’t peer-review this paper: I would have asked for several more experiments. Still, overall the actual association between Vpu and invariant chain looks fairly convincing, and there does seem to be an effect (though not a terribly impressive one) on overall MHC class II surface expression and on antigen presentation.
This is not the first time a viral protein has been shown to affect MHC class II. The human cytomegalovirus proteins US23 and US34 both affect MHC class II as well as MHC class I; herpes simplex virus is supposed to attack several steps in MHC class II antigen processing,5 again as well as MHC class I; and there are a handful of other examples. Aside from the HCMV US2 story, few have been studied in any detail, as far as I know, and in no case is their role in pathogenesis known.
HIV budding from a lymphocyte
So how might it make sense for a virus to block MHC class II antigen presentation? There are some ways in which this would make sense, but I don’t think any of them are particularly good answers.
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