T cells & herpes simplex
CTL (green) and HSV-infected cells (red)
(from Akiko Iwasaki)

Last time I talked about herpesvirus immune evasion of cytotoxic T lymphocytes, I cautiously wondered if there might be a theme emerging: Do these genes mainly help the virus with latent infection?

Immune evasion of CTL seems to be pretty much universal among the millions of different herpesvirus species — at least, as far as I know, in every case where people have looked for it, the virus has some way of blocking antigen presentation. Although other virus families also block antigen presentation (HIV, some poxviruses, and human adenoviruses are probably the best known instances), immune evasion isn’t as universal among those other families.

For example, although human adenoviruses mostly have immune evasion function, adenoviruses of other species do not (as far as we can tell); and for that matter not even all human adenoviruses have the ability to block antigen presentation. What’s more, there is a trend for those non-herpesvirus viruses that do evade CTL, to also establish long-term latent or persistent infection.

A recent paper from Frank Carbone’s lab1 offers a little more, indirect, support for this theme. They asked what CTL actually do to herpes simplex virus in the initial infection.

HSV-infected ganglionWe usually blithely call CTL “antiviral lymphocytes”, but what exactly does that mean for specific virus infections? For example, I’ve previously pointed out experiments that show that CTL have more than one way of clearing away virus infections — they can use cytokine secretion as well as, or instead of, cell lysis, as their weapon, which opens up the opportunity for activity over a broad range rather than one cell at a time. In another example, Luis Sigal’s lab has shown that CTL can protect against extromelia (mousepox) infection at a very early stage, by blocking the virus’s spread from the skin to the liver, cutting them off at the bottleneck of the lymph through which the virus intially spreads.

On the other hand, herpes simplex virus often seems to do just fine even when CTL are present. The virus sets up an initial infection in the skin, and rapidly tracks up through neurons to ganglia, where it sets up a latent infection. By the time CTL are up and running, the virus is comfortably snuggled down in the neuron, shutting down all its protein expression to the point where CTL don’t see it very well. Even if you have an active CTL response already, the virus seems to be able to get in to the neurons and set up latency anyway.

So what do CTL do to herpes simplex? Carbone’s lab set up mice with and without specific anti-HSV CTL, and infected them with the virus. As you’d expect (and as has been shown lots of times in the past) the CTL markedly reduced the amount of virus replication and shedding, but did not prevent the virus from setting up a latent infection.

Though the presence of herpes-specific effector CD8+ T cells early during viral challenge attenuated the primary infection and prevented the development of disease, these cells failed to block the skin to nervous system transmission of the virus, and hence substantial latent infections were established in the face of this CTL immunity.

(My emphasis.) How come? Part of the answer seems to be that the CTL didn’t respond quite fast enough. 2 Virus infects the skin, replicates, and moves up into neurons in about 24 hours. (If they surgically removed the infected skin prior to 24 hours after infection, neurons weren’t infected; if they removed the infected region more than 24 hours after infection, neurons were infected.) CTL, on the other hand, move into the infected region of skin within about 15 hours of infection. At this point the CTL start to shut down virus replication; but the window of opportunity, as you can see, is very narrow. The CTL need to shut down the virus in the skin very rapidly, and to very low levels, within just a few hours of entering the site of infection.

In fact, if you start off with a relatively small amount of virus, then CTL can shut the replication down enough to make a difference.  It’s mainly when there’s a lot of virus to start with that the CTL can’t get the virus down under some threshold level that allows efficient latent infection:

Thus, virus-specific CTL can reduce the average viral copy number of the residual latent infection, but this is only achievable when a substantial attenuation of the skin infection is observed.

Trigeminal ganglionThere are a bunch of fascinating points that arise from this work. First, it helps account for the fact that superinfection with herpes simplex is actually quite rare — that is, if you’re infected with HSV already, then you’re unlikely to get re-infected with a second virus. Normal exposure to HSV probably is at a very low level, with only a handful of virions entering the skin; it’s more like the low-range infection in Carbone’s experiments than the high-range, where they put in some 10 million virions, and at the low range, CTL can move in and check the initial infection fast enough to make a difference.

Second, a critical point about these experiments is that they were done in the absence of CTL evasion. That’s because there experiments were done in mice, and the HSV immune evasion molecule ICP47 doesn’t work in mice, as opposed to in humans.

One of the puzzling things about immune evasion genes, to me, has been how ineffectual they seem to be in authentic infections. But these experiments suggest if your interest is in establishing latency, then immune evasion doesn’t need to be hugely effective: It just needs to keep the window open a crack for a few more hours, letting the virus replicate through the first wave of CTL invasion. If ICP47 can hold off the CTL for an extra 8 hours, then it’s probably done its job, allowing HSV to set up a latent infection and thus reactivate and infect new hosts on and off over the next 60 or 70 years.

So, even though this paper really didn’t look at immune evasion per se, I think it does offer some support for the concept that (for herpesviruses, anyway) immune evasion really isn’t for the acute infection at all.  Instead, it’s a mechanism to help the virus establish latent infection.


  1. Wakim, L.M., Jones, C.M., Gebhardt, T., Preston, C.M., Carbone, F.R. (2008). CD8+ T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunology and Cell Biology DOI: 10.1038/icb.2008.47[]
  2. I wonder whether they miigh have seen a faster response if they had started with skin-specific T cells, though.[]