Baines HSV
Electron tomogram of HSV1

Latency is one of the defining characteristics of the herpesviruses, and it’s also one of the least well understood — especially the role of immunity in latency.

One of the open questions about HSV is what latency really means, in vivo. We know that the virus enters neurons, and then seems to pretty much shut down all its proteins. That should make it mostly invisible to the immune system (or at least to the adaptive immune system). Yet HSV reactivates intermittently (those recurrent cold sores), and it’s generally agreed that reactivation is associated with mild immune suppression. 2

So one question is: If there are no viral proteins being expressed, how can the virus evaluate the status of the immune system outside the neuron? How does the virus know there’s immune suppression out there?

There have been, I think, three general answers to that question:

  1. Viruses reactivate randomly from the neurons, and constantly send out probes into the body. According to this idea, it’s not that the virus needs immune suppression to reactivate, but rather it’s reactivating all the time; it needs immune suppression for the reactivations to take root and become detectable.
  2. Viruses do in fact have some proteins expressed even during latency, and can sense the state of the immune systems that way. (A variant on this is the possibility that non-protein components are doing the sensing. We know that some viral RNAs are present during latency.)
  3. It’s the immune system that keeps the virus latent. Take away the immune system, and out pops the virus.

These are not mutually exclusive possibilities, though it’s likely that just one factor is the main cause.

CD8 in ganglia, Khanna et al 2003In early days, it was tentatively believed that (3) was not likely — you’d need to have some signal to draw the immune response to the appropriate neuron (especially because of course T cells are normally kept away from the brain) and because HSV doesn’t express proteins during neuronal infection, where’s your antigen target? On the other hand, it’s been known for a while that in mice, at least, ganglia that are latently infected with HSV show signs of chronic inflammation.3 It’s never been entirely clear, at least to me, if latent infection in the mouse is precisely like latency in humans, but recently similar findings have been made in human ganglia, even in the complete absence of detectable viral proteins.4

Chronic inflammation means there are immune cells hanging around inside the ganglia. What are these cells? Are they specific for the virus, or are they non-specific cells that have been attracted into the area by the general inflammation? A while ago, I mentioned evidence that antigen-specific T cells are specifically allowed in to the brain, and it was shown a few years ago that in mice the infiltrating cells were antigen-specific, for herpes simplex antigens. (The image at right shows infiltrating T cells in an infected ganglion, from that paper.5) Now, it turns out that the same is true in humans:

CD8+ T cells are selectively located in close vicinity to HSV-1 latently infected neuronal cell bodies. … These results support the recent diversion from the old dogma that HSV-1 latency is an antigenic silent infection. … The collective data argue that the neuron-interacting T cells are most likely HSV-1 specific and recognize those latently infected neurons that intermittently express low amounts of viral proteins below levels detectable by using biochemical means or a particular subset of neurons in which HSV-1 has reactivated from latency. 6

The obvious (though not necessarily correct!) conclusion is that these T cells surrounding infected neurons prevent HSV reactivation from latency, and only when the surrounding T cells are reduced in number or effectiveness — during immunosuppression, in other words — can the virus escape long enough to set up a reactivation.

Interestingly enough, this seems to not be true for Varicella-Zoster virus! VZV (another herpesvirus, of course — chicken-pox and shingles) also establishes latency in the same kinds of ganglia, yet there were no VZV-specific infiltrating T cells. “Neurons latently infected with VZV appear to be invisible for T cells, whereas HSV-1 has adopted mechanisms to impede cytotoxic T lymphocyte-mediated eradication from their latency stronghold.”7

  1. Electron tomogram of a HSV nucelocapsid completing envelopment , from Baines, J. D., C. E. Hsieh, E. Wills, C. Mannella, and M. Marko. 2007. Electron tomography of nascent herpes simplex virus virions. J Virol 81: 2726-2735.[]
  2. This is actually not very solidly proven, in my mind, though it’s widely accepted — but let’s take it as a given that reactivation from latency requires immune suppression.[]
  3. For example, Shimeld C, Whiteland JL, Nicholls SM, Grinfeld E, Easty DL, Gao H, Hill T. (1995). Immune cell infiltration and persistence in the mouse trigeminal ganglion after infection of the cornea with herpes simplex virus type 1. J Neuroimmunol 61:7-16 ; and Liu T, Tang Q, Hendricks RL. (1996). Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. J Virol 1996, 70:264-27[]
  4. Theil, D., T. Derfuss, I. Paripovic, S. Herberger, E. Meinl, O. Schueler, M. Strupp, V. Arbusow, and T. Brandt. 2003. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response. Am J Pathol 163: 2179-2184.[]
  5. Khanna, K. M., R. H. Bonneau, P. R. Kinchington, and R. L. Hendricks. 2003. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia. Immunity 18: 593-603. []
  6. Verjans, G. M., Hintzen, R. Q., van Dun, J. M., Poot, A., Milikan, J. C., Laman, J. D., Langerak, A. W., Kinchington, P. R., and Osterhaus, A. D. (2007). Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia. Proc Natl Acad Sci U S A 104, 3496-3501. []
  7. Could this be the elusive function of immune evasion molecules? Since the HSV immune evasion protein ICP47 does not work in mice, that can’t be the only answer, but it may be a factor in humans.[]