Adenovirus infecting HeLa cells
Adenovirus infecting HeLa cells

I’ve quoted before that “the stupidest virus is smarter than the smartest virologist”. Adenoviruses are far from the stupidest viruses, and even after 55 years of study, and nearly 40,000 papers in PubMed, adenoviruses still throw surprises at us on a regular basis. Last week, while talking about herpesviruses, I added that “the other virus families that are known to evade MHC class I are human adenoviruses, which now turn out to establish true latency”. True latency has been hinted at for a while, but Linda Gooding’s group has added much more support for it in a paper in press at J Virol.1

Adenoviruses are very, very common viruses, both in humans and in many other species. In humans there are over 40 different adenovirus “species”, mostly causing cold-like symptoms and mild gastrointestinal disease. Occasionally, and perhaps with increasing frequency, there’s a more or less widespread outbreak of moderate disease, but in general these guys are not huge problems as far as mortality in immune-competent people.

As well as being common, many adenovirus species are pretty easy to grow in cultured cells, and so it’s not surprising that they were isolated and described a long time ago. In fact, the first identification of adenoviruses was as an accidental isolation in 1953, when Rowe et al noticed that the tonsil cell cultures they were growing were showing signs of viral infection.2 Since then, adenoviruses have been used as models for a huge number of cell biology functions (the Nobel on splicing came from work on adenoviruses, just as one example), as well as cancer biology and lots of other things; adenoviruses have also been used as workhorses for the viral vector field, moving into gene therapy as well.

Tonsillectomy (Greenfield Sluder: 1923)

If you look in lots of tonsils, you’ll find lots of adenovirus; something like 80% of samples turn up positive. 3 That’s much higher than the disease rate, of course, and it’s also much higher than any plausible incidence rate — that is, those can’t all be new infections, in the past week or so, that simply haven’t been cleared by the immune system. That means that adenoviruses must be able to persist for some fairly significant period — months to years — after their initial infection, without causing symptoms.

This long-term persistence by adenovirus is one of its most characteristic, um, characteristics, but it’s been completely mysterious. (If you don’t believe me, here’s what Bill Wold and Marshall Horwitz say in the latest version of the authoritative Fields Virology: “We really do not understand whether and how adenovirus persists at very low levels in humans … “)

For adenoviruses, usually the term “persistence” is used, rather than latency, because “latency” has a specific meaning: Basically, a latent virus is still present at the genome level, but isn’t capable of forming a new virus particle. Herpesviruses are the main viruses that are known to do this. Some retroviruses set up latent infection by intergrating into the host genome, but that’s a little different story. Herpesviruses can maintain their own genomes in the latently-infected cell, but in a form that’s independent of the host genome. As I’ve noted before, this latency may be tightly linked to immune evasion functions. The other option is mere “persistence”, where presumably the virus would remain in a replicating form, and would be capable of forming a new virus, perhaps at a very slow turnover rate of replication.

A handful of papers have suggested that adenoviruses might establish truly latent state4, but this new paper from Gooding’s lab1 is the most convincing I’ve seen yet. They compared infectious virus to the amount of viral DNA — that is, to viral genomes — and concluded that “only a small amount of viral DNA is present as infectious virus, even in samples with large amounts of viral DNA. … time in culture also appears to activate latent virus in the tissues, which was detected by transferring “activated” lymphocyte-derived virus onto permissive A549 cells.” (This is exactly how you detect latent infection by herpesviruses, in general — you transfer latently-infected tissue onto other cells, and over time the virus reactivates from latency to become infectious virus, and shows up on the permissive cells.) They showed that on initial exam the virus wasn’t making any transcript, again a requirement for true latency, and that over time transcripts began to appear as the virus reactivated.

As a side note, Gooding notes dryly that sloppy technique may be part of the reason adenoviruses were so often found in tonsil explants, a suggestion I hadn’t heard before.

Reports of infection of laboratory workers in the early adenovirus groups suggest that some exogenous contamination might have elevated the frequency with which live virus was found in these studies.

Finally, Gooding re-emphasizes the same point I’ve made here:

Furthermore, like all DNA viruses that form latent or persistent infections, human species C adenoviruses encode a variety of gene products, primarily within the E3 transcription unit, that function to counteract host anti-viral defense mechanisms. We have previously reported that the E3 promoter is up-regulated when cells are exposed to signals that activate T lymphocytes. Hence, it appears likely that the immune evasion strategies of these viruses are directed toward protecting the T lymphocyte from destruction during the period of viral activation from latency.

(My emphasis) As far as that goes, it’s particularly interesting to me that only human adenoviruses, and not even all of them, have MHC class I immune evasion functions. Does that mean that that particular function is less critical for latency, or does it mean that non-human adenoviruses don’t establish true latency (even in these humans, they really only found group C adenoviruses to be latent, though that may just reflect tissue preferences), or what?

  1. C. T. Garnett, G. Talekar, J. A. Mahr, W. Huang, Y. Zhang, D. A. Ornelles, L. R. Gooding (2008). Latent species C adenoviruses in human tonsil tissues Journal of Virology DOI: 10.1128/JVI.02392-08[][]
  2. Rowe WP, Huebner RJ, Gillmore LK, et al. Isolation of a cytopathic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proceedings of the Society for Experimental Biology and Medicine. 1953;84:570-573. []
  3. Garnett CT, Erdman D, Xu W, et al. Prevalence and quantitation of species C adenovirus DNA in human mucosal lymphocytes. J Virol 2002;76:10608-10616. []
  4. Neumann R, Genersch E, Eggers HJ. Detection of adenovirus nucleic acid sequences in human tonsils in the absence of infectious virus. Virus Res 1987;7:93-97. []