The blocking molecule could be secreted, so it affects neighboring antigen-presenting cells. This would actually be a very simple answer, except that none of the described cases do anything like this; they all affect MHC class II on the infected cell only and are not secreted. (I believe there are bacterial proteins which act somewhat like this.)
(2) The virus infects enough antigen-presenting cells to impact the overall CD4 response. I think this is the most common assumption, but … Eh. Maybe. In the early stages of infection with HIV or HCMV, a significant minority of macrophages and dendritic cells might be infected, but I’m dubious that there would be enough to have much of an effect — even less so for herpes simplex virus, which isn’t known for infecting these kinds of cells much at all.
(3) The virus is protecting against direct recognition by CD4 cells, rather than classical helper-type activity. While MHC class II mainly presents peptides from extracellular sources, the pathway presents a fair amount of intracellular antigen as well,6 and CD4 T cells can be cytotoxic, just like MHC class I-restricted CD8 T cells. This is actually my favorite explanation, but I’m not blown away by it; I’m not sure how common cytotoxic CD4 cells are, for one thing. For another, the rather wimpy effect of Vpu on MHC class II expression that Hussain et al showed here, doesn’t strike me as sufficient to prevent CD4 recognition — though they didn’t test for that, so it’s still a possibility.
(4) The effect on MHC class II is an irrelevant side-effect of the true function of the protein, such as attacking MHC class I. MHC class II molecules are awfully similar to MHC class I (see this post for examples), so maybe the HCMV molecules are binding by accident. Similarity between class I and II doesn’t explain binding the invariant chain, but invariant chain was shown to interact with MHC class I molecules7 as well as class II — a finding no one has known what to do with in the 12-plus years since it was described — so again, maybe Vpu is “really” targeting MHC class I, and the effect on MHC class II is a side-effect. Or there could be some other effect on viral replication or assembly, it doesn’t have to be related to MHC class I.(5) Similar to (4) — maybe the effect on MHC class II offers a very minor protection for the virus, but it comes cheap because the virus has already developed machinery to attack the closely-related MHC class I pathway. In this argument the payoff of attacking MHC class II is small, but the investment in expanding the function of anti-class I molecules to also interact with class II is small as well, so why not go ahead? (Or, less teleologically, having evolved anti-MHC class I molecules, very minor changes in their sequence allowed an effect on MHC class II as well.)
(6) MHC class II has some effect on viral infection other than through interaction with CD4 T cells, and it’s those (unknown) effects that the viruses are defending themselves against. This is the most intriguing possibility, and the reason I keep going back and studying these papers; but there’s not a lot of actual evidence for it.
(2) The virus infects enough antigen-presenting cells to impact the overall CD4 response. I think this is the most common assumption, but … Eh. Maybe. In the early stages of infection with HIV or HCMV, a significant minority of macrophages and dendritic cells might be infected, but I’m dubious that there would be enough to have much of an effect — even less so for herpes simplex virus, which isn’t known for infecting these kinds of cells much at all.
(3) The virus is protecting against direct recognition by CD4 cells, rather than classical helper-type activity. While MHC class II mainly presents peptides from extracellular sources, the pathway presents a fair amount of intracellular antigen as well,6 and CD4 T cells can be cytotoxic, just like MHC class I-restricted CD8 T cells. This is actually my favorite explanation, but I’m not blown away by it; I’m not sure how common cytotoxic CD4 cells are, for one thing. For another, the rather wimpy effect of Vpu on MHC class II expression that Hussain et al showed here, doesn’t strike me as sufficient to prevent CD4 recognition — though they didn’t test for that, so it’s still a possibility.
(4) The effect on MHC class II is an irrelevant side-effect of the true function of the protein, such as attacking MHC class I. MHC class II molecules are awfully similar to MHC class I (see this post for examples), so maybe the HCMV molecules are binding by accident. Similarity between class I and II doesn’t explain binding the invariant chain, but invariant chain was shown to interact with MHC class I molecules7 as well as class II — a finding no one has known what to do with in the 12-plus years since it was described — so again, maybe Vpu is “really” targeting MHC class I, and the effect on MHC class II is a side-effect. Or there could be some other effect on viral replication or assembly, it doesn’t have to be related to MHC class I.(5) Similar to (4) — maybe the effect on MHC class II offers a very minor protection for the virus, but it comes cheap because the virus has already developed machinery to attack the closely-related MHC class I pathway. In this argument the payoff of attacking MHC class II is small, but the investment in expanding the function of anti-class I molecules to also interact with class II is small as well, so why not go ahead? (Or, less teleologically, having evolved anti-MHC class I molecules, very minor changes in their sequence allowed an effect on MHC class II as well.)
(6) MHC class II has some effect on viral infection other than through interaction with CD4 T cells, and it’s those (unknown) effects that the viruses are defending themselves against. This is the most intriguing possibility, and the reason I keep going back and studying these papers; but there’s not a lot of actual evidence for it.
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