Painting of TcR interacting with artrificial membranes by Raghuveer Parthasarathy
TcR interacting with artificial membrane1

Earlier this week I talked about the phenomenon of viruses that downregulate MHC class II. The “purpose” of this blockade is kind of unclear to me, because the immunity driven by MHC class II is not focused on the cell it’s attached to, but rather spills out broadly over a wide area; it seems that a virus would have to very rapidly infect a very large number of MHC class II-expresing cells to have much effect on the anti-viral immune system.

One possible explanation is that the downregulation may be only peripherally related to MHC class II-based immunity. Instead, the virus could be simply going about its cell-biological business and either targeting MHC class II as an accidental side-effect, or because of some function of MHC class II that isn’t directly related to immunity. Here’s a parallel case that may help think about the problem.

The paper is
Sullivan, B.M., Coscoy, L. (2007). Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein. Journal of Virology, 82(2), 602-608. DOI: 10.1128/JVI.01571-07

The T-cell receptor (TcR) is what recognizes MHC class I or II. Human herpesvirus 6 (HHV6) infects T helper (CD4) cells and (depending on viral strain) also does a number of things to modulate the immune system.2 Sullivan and Coscoy show here that the virus also down-regulates the TcR on infected T cells. (It’s altogether a more solid paper than the last one I mentioned, with nice experiments that directly show what’s happening to the TcR: “HHV-6 U24 protein inhibits CD3 recycling to the cell surface and, as a consequence, downregulates CD3 cell surface expression and prevents T-cell activation.“)

Sullivan & Coscoy Fig 4
U24 blocks CD3ε access to Rab11 recycling endosomes.3

At first glance this raises exactly the same question as does Vpu’s effect on MHC class II. How does reducing TcR on infected cells benefit the virus? The infected T cell will be less able to recognize its target, but what are the odds that its target is HHV6? Pretty minimal; there are (at least) tens of billions of different TcRs and only a handful of them recognize any particular antigen. The virus might be causing generalized immune suppression if it infects a large fraction of the T cells, but that’s not a particular benefit for the virus. If HHV6 specifically infected cells with TcRs that are specific for the virus then this would be a targeted immune evasion technique, but as far as I know there’s no evidence for this, nor is there an obvious mechanism by which HHV6 could target antigen-specific CD4 T cells.

There is, however, a nice explanation for TcR downregulation that doesn’t involve direct effects on T cell recognition. HHV6 (like all herpesviruses) has two choices when it infects a cell. It can either enter lytic replication — replicating the genome, producing more viruses, and eventually destroying the infected cell — or enter latency — a long-term, perhaps life-long, infection with minimal protein expression and little if any effect on the infected cell. As with any virus, the more prepared a cell is to replicate, the easier it is for a virus to replicate it’s own genome. T cells that receive a signal through their TcR become activated4 and divide very rapidly. In this environment, it’s very easy for HHV6 to replicate — that is, to enter lytic replication and kill the cell, releasing more viruses into the system.

Human herpesvirus 6 (HHV6)
Human herpesvirus 6

Probably HHV6 downregulates the TcR “because” it prevents its host from becoming activated by whatever its random antigen is. That prevents the virus from entering lytic replication and allows it to enter a persistent state, where it can hang about and await the best opportunity to infect a new person.

I know of one other viral protein that downregulates the TcR — the herpesvirus saimiri Tip protein 5 — and there seems to be controversy6 over whether this protein activates T cell signalling (potentially driving the virus into lytic replication) or blocks it (preventing lytic replication and facilitating persistence). 7 The original paper describing the TcR downregulation found that Tip blocked signaling, and proposed the same explanation as Sullivan and Coscoy:

… these associations ultimately block lymphocyte receptor signal transduction. … these interactions likely play an important role in the establishment and maintenance of HVS persistent infection by protecting infected cells from surveillance by the immune system. In fact, animals infected with recombinant HVSΔTip have been shown to have higher levels of cell-associated infectious virus titer compared to other recombinant HVS.

So in this case the downregulation of the TcR (a quintessentially immune molecule) apparently isn’t directly related to immune evasion, but is a way of switching between the lytic and the persistent lifestyles. (It’s also a reminder of the fairly obvious point that we shouldn’t think of viruses as blind replicators, desiring nothing more than maximal replication. At least some viruses have a range of lifestyle options, and can switch between them quite comfortably.)

I still don’t see a direct analogy to the MHC class II downregulation imposed by the HIV Vpu protein. but it’s an example of why we shouldn’t get too focused on single causes and single functions. Life is more complicated than that.


  1. By Raghuveer Parthasarath, then in the Groves lab[]
  2. Lusso, P., 2006. HHV-6 and the immune system: mechanisms of immunomodulation and viral escape. Journal of Clinical Virology, 37(Supplement 1), p.S4-S10. doi:10.1016/S1386-6532(06)70004-X []
  3. Sullivan & Coscoy, Fig 4[]
  4. I am simplifying immensely![]
  5. Park, J. et al., 2002. Herpesviral Protein Targets a Cellular WD Repeat Endosomal Protein to Downregulate T Lymphocyte Receptor Expression. Immunity, 17(2), p.221-233. doi:10.1016/S1074-7613(02)00368-0 []
  6. Brinkmann, M.M. & Schulz, T.F., 2006. Regulation of intracellular signalling by the terminal membrane proteins of members of the Gammaherpesvirinae. J Gen Virol, 87(5), p.1047-1074. DOI 10.1099/vir.0.81598-0[]
  7. I’m more convinced by the argument for blocking signaling, but only because of the very bad reason that I know the people involved. I haven’t looked at the papers pro and con very carefully.[]