|“Adenovirus” (by Mapposity)|
There are two aspects about virology that constantly amaze me: How much we know about viruses, and how little we know about viruses.
Adenovirus research offers examples of both. Adenoviruses are probably among the best-studied virus groups.1 We really do know an amazing amount about them. But it was only last year that Linda Gooding’s group offered the most convincing demonstration yet that adenoviruses actually establish a truly latent infection — a really basic aspect of their lifestyle, 2 and a new paper from her group3 is looking at some equally-basic implications of that finding. (I talked about Gooding’s earlier latency finding here.)
It’s been known pretty much since day 1 that adenoviruses persistently infect tonsils;4 that was why they were first isolated, when the virus grew out of apparently-normal tonsil tissue in culture. The critical distinction is between mere “persistence” and true “latency”. In a latent infection, the virus shuts down production of new viruses, and is maintained basically as DNA within the host cell. Persistence is cruder — the virus continues to replicate, but at a low level that balances its destruction. Simplistically, latency is a destruction-free process, while persistence can include viral and cellular destruction.
Adenoviruses establish their latency in tonsils, which of course have lots of lymphocytes, but we usually think of adenoviruses as infecting epithelial-type cells, or hepatocytes, or whatever. Clinically, these guys typically cause cold-type symptoms, which you tend to get from fairly superficial infections of the respiratory tract lining. We don’t tend to think of adenoviruses as effective infectors of lymphocytes, but it turned out that their latent infection was, in fact, in T lymphocytes. It looks like adenoviruses have one cell type (epithelial-type cells) for a lytic infection that leads to shedding of infectious virus, and another cell type for latent infection, allowing the virus to remain in the host and potentially re-infect an epithelial type later on.
Accordingly, Gooding and her team set up infections of cultured T lymphocytes in vitro, to see what would happen. In particular, they wanted to know whether, and how, the viral replication cycle would be controlled; and whether and how the host cell would be affected by the infection. I will skip over most of their findings and and highlight a couple that surprised me:
(1) The “Occupied!” sign. To get into a cell, adenoviruses usually need to bind to their cellular receptor, the CAR receptor.5 But latently-infected cells almost permanently shut off this receptor. For hundreds of days after the initial infection, cells express little or no CAR. The latent virus doesn’t want any competition; it has found a congenial long-term environment, and it doesn’t want some interloper infecting its cozy cell and perhaps destroying it.
There seem to be several mechanisms for the shutdown, but at least part of it is that the virus apparently permanently modifies the host DNA:
CAR synthesis and expression remained repressed even after the viral genome was lost (Fig. 8 and data not shown), suggesting a virus-induced epigenetic change to the cells that does not require the continued presence of the virus.3
And in fact the CAR isn’t the only thing to be modified for this purpose:
Even when CAR levels were restored by transduction with a CAR-containing retrovirus, the previously infected cells could not be reinfected3
We don’t know how the latent viruses were blocking superinfection, but it’s clear that the latent viruses really don’t want company.
(2) Rearranging the furniture. The latent virus doesn’t stop at hanging an “occupied” sign; it modifies its host cell in other ways as well, apparently again by long-term or even permanent epigenetic modification of the DNA. That means that even after the virus itself is altogether gone, not even latently present, there are modified cells hanging about:
Remembering that adenoviruses infect just about everyone, that may mean that we’re all walking around carrying cells that are tagged and functionally altered by these viruses.
There’s been speculation for many years that adenovirus infection may underlie some forms of human tumors. One argument against this has been that there’s no evidence of adenovirus DNA in tumors, for the most part.6 (One rule of thumb in determining if a virus is actually causing a tumor is if it’s actually present in the tumor.) But of course, if adenoviruses leave a permanent scar on cellular DNA that lasts longer than the virus itself, this may not be relevant:
One compelling reason to gain an understanding of this nonlytic infection is the likelihood that adenovirus gene products cause damage to the host cell genome. … While these functions are irrelevant to the lytic infection of epithelial cells where all infected cells die, they are of serious concern when infected lymphocytes have carried the viral genome and survived. … Despite this normal appearance, the cells display altered gene expression long after the virus is lost.3
- There are over 40,000 papers on adenoviruses, or at least mentioning them, in PubMed.[↩]
- To be fair, it’s been suspected for decades that they do go latent, but that was the first time it was actually proven.[↩]
- Zhang, Y., Huang, W., Ornelles, D., & Gooding, L. (2010). Modeling Adenovirus Latency in Human Lymphocyte Cell Lines Journal of Virology, 84 (17), 8799-8810 DOI: 10.1128/JVI.00562-10[↩][↩][↩][↩]
- I’m going to limit this discussion to the Group C adenoviruses — the latency concept may be true for other groups of adenoviruses but that hasn’t been directly shown.[↩]
- “CAR” stands for the “Coxsackie B virus and Adenovirus Receptor”. Can anyone guess what other virus uses this receptor? Bueller? Anyone?[↩]
- Also, the epidemiological links between tumors and adenoviruses are not very strong, at least in humans.[↩]