J Virol cover, Human foamy virusOne of the interesting things about the retrovirus family is that it contains some of the most lethal viruses we know of, and also some of the least harmful. For obvious reasons, the lethal family members (HIV) get lots of recognition, while their harmless cousins get little more than an occasional mention. There are more — far more — articles on HIV in the past two weeks, than there have been on the spumaviruses in the past 50 years. In fact, it’s only very recently that people have demonstrated why the spumaviruses are actually harmless. 1

HFVSpumaviruses, or foamy viruses, infect many species — though not, apparently, humans,2 even though they’re common infections of old world monkeys and apes. Normally I’d assume that the lack of human spumaviruses was simply because nobody has looked hard enough, but I think in this case that simple answer isn’t true; lots of groups have been looking and haven’t found any evidence. Perhaps they’re only found in a limited number of tissues, or under certain circumstances, but I believe the work has been pretty thorough. Indeed the work has been thorough enough to turn up people infected with spumaviruses, but only because of cross-species infections from apes and so on3 — even though the detection methods are apparently adequate, there’s no evidence for human to human transmission.4

 Meiering & Linial, J Virol 2003Anyway, spumaviruses infect many species, and in all of them appear to be completely harmless. 5 Yet in tissue culture, these viruses are deadly, rapidly killing infected cells.6 I’ve always assumed that the reason spumaviruses are harmless in an authentic infection is that the host immune system controls the virus, preventing it from replicating so that its host cells don’t get killed by the virus. This turns out not to be the case.

You may be wondering, by the way, why anyone should care why they’re harmless. Why not accept that they are harmless, and concentrate on dangerous pathogens? Apart from being interesting in their own right, I think part of the answer is probably obvious — is there some underlying mechanism that can be applied to a different pathogen, to make it apathogenic?

But another part of the question is viral vectors. There’s intense interest in developing viruses as gene therapy vectors, and one of the obstacles to many of the present candidate vectors — adenoviruses, adeno-associated viruses, lentiviruses, and so on — is that the vector is intrinsically harmful. To use these vectors to treat disease you need to render the virus harmless, first and foremost; and almost ineviatably, this reduces the virus’s ability to infect, which is why you want it in the first place. If you can start with a virus that’s already harmless, then you’re halfway to your goal from the start. There’s increasing interest in developing spumaviruses as gene therapy vectors,7 and so we really would like to know why they are harmless.

Murray et al. 2008, Fig 2It turns out, surprisingly (to me, anyway) that spumaviruses are probably just as cytopathic in their natural host, as they are in cultured cells. However, they strictly limit their replication to expendable cells, that are going to die anyway: epithelial cells that are about to be sloughed off and shed anyway.

… FV replication is limited to cells at a very late stage of epithelial cell differentiation, when the cells are about to be shed from the tissue. … The most superficial terminally differentiated cells in the epithelial cell layer turn over in about 3 hours. Thus, the limitation of viral replication to a relatively expendable, superficial cell type could account for the innocuous character of FV infection in vivo. … The contrasting in vitro situation, in which FV infection spreads rapidly and is cytopathic to the entire culture, may be an artifact of culture systems that do not represent the differentiated cell types or cell turnover rates within mucosal epithelial tissues.

My first reaction is that this isn’t very encouraging for spumaviruses as gene therapy vectors, but that’s not necessarily true; the viruses can infect many other tissues, though probably latently, and that may well be perfectly adequate for gene therapy.

I’ve pointed out in the past that pathogens don’t necessarily evolve toward reduced virulence; rather, pathogens evolve toward efficient transmission, which may or may not involve a healthier host. This is a lovely example of efficient transmission coupled with reduced virulence:

This mechanism of viral replication promotes efficient virus transmission via shed cells while limiting viral replication to a superficial site and thus minimizing host tissue damage.

The authors make a comparison to some other virus families that do something quite similar — herpesviruses and papillomaviruses, which as a group often infect one cell type latently but undergo lytic, active replication in differentiated skin cells. They say

… herpesviruses and papillomaviruses, with similar replication patterns, are also ancient viruses. Differentiation-specific viral activation within differentiated cells of the oral mucosa or the skin arose independently in these diverse virus families. … Indeed, in the majority of infections, none of these viruses leads to pathogenic sequelae.

What they mean by “ancient” here, I think, is that they’ve co-evolved with their hosts for a long time, and are well adapted. Herpes and papillomaviruses are more often pathogenic than are spumaviruses, I think, but it’s an interesting suggestion.

  1. Murray, S.M., Picker, L.J., Axthelm, M.K., Hudkins, K., Alpers, C.E., Linial, M.L. (2008). Replication in a Superficial Epithelial Cell Niche Explains the Lack of Pathogenicity of Primate Foamy Virus Infections. Journal of Virology, 82(12), 5981-5985. DOI: 10.1128/JVI.00367-08[]
  2. The so-called human foamy virus that was isolated in the 1970s is actually a chimp virus that was probably acquired through interspecies transmission.[]
  3. Calattini S, Betsem EB, Froment A, Mauclere P, Tortevoye P, Schmitt C, Njouom R, Saib A, Gessain A (2007) Simian foamy virus transmission from apes to humans, rural Cameroon. Emerg Infect Dis 13:1314-1320.[]
  4. Boneva RS, Switzer WM, Spira TJ, Bhullar VB, Shanmugam V, Cong ME, Lam L, Heneine W, Folks TM, Chapman LE (2007) Clinical and virological characterization of persistent human infection with simian foamy viruses. AIDS Res Hum Retroviruses 23:1330-1337.[]
  5. It’s possible that they are associated with very rare disease and because humans aren’t involved there isn’t the intense search for cause that human disease often leads to; but the virus is really very common, infecting at least a third of cats, cattle, and primates in the wild; at that frequency of infection, even rare diseases would probably be picked up in cats or cattle.[]
  6. Saib A (2003) Non-primate foamy viruses. Curr Top Microbiol Immunol 277:197-211.[]
  7. For example, Bastone P, Romen F, Liu W, Wirtz R, Koch U, Josephson N, Langbein S, Lochelt M (2007) Construction and characterization of efficient, stable and safe replication-deficient foamy virus vectors. Gene Ther 14:613-620.
    Also, reviewed in Rethwilm A (2007) Foamy virus vectors: an awaited alternative to gammaretro- and lentiviral vectors. Curr Gene Ther 7:261-271.[]