Friday, 5 July 2013

What's Killing the Koalas?
My current employer made his name working on a retrovirus: Jaagsiekte sheep retrovirus (JSRV). JSRV is a betaretrovirus whose greatest claim to fame is killing Dolly the sheep, but it has revealled many aspects of sheep and retrovirus biology. One of the attributes most associated with viruses is that they're obligate intracellular parasites: without a cell to replicate in, viruses are often little more than a bunch of molecules. Retroviruses take this to the extreme and insert into a cells genomic DNA in order to replicate. At it's simplest this involves the virus like any other infecting a somatic cell, intergrating into the cellular DNA, replicating and exiting. This is the 'exogenous' form. 

Alternatively, if the cell happens to be a germ cell, from which sperm or eggs are produced as a precursor to another individual, the retroviral DNA will be inherited by Mendelian inheritance as for any other gene. When this happens, the virus is now regarded as being 'endogenous'.

In the last few years a type-C retrovirus, Koala retrovirus (KoRV), has been linked to the development of Koala immunodeficiency syndrome (KIDS). As the term suggests, KIDS results in a depleted immune system, resulting in enhanced vulnerability to infectious diseases and cancers. KIDS has become a prominent killer of koalas, particularly those in captivity, where the majority of studies have been performed. KoRV's closest relative appears to be gibbon ape leukemia virus (GALV) which, like KoRV, causes lymphomas and leukemia.

KoRV represents an example of a very young endogenisation event, with the intergation event thought to be only around 100 years ago, and the integrated copies are able to generate infectious viruses. A recent paper in PNAS describes the isolation of a variant of KoRV in San Diego and Los Angeles zoos (Xu et al 2013). All of the koalas at the zoos contained the endogenised form of KoRV. However, in six koalas at Los Angeles zoo, including 3 that died, they found an additional, slightly different, KoRV sequence (KoRV-B, as opposed to the original KoRV-A). The majority of the changes were in the U3 region of the long terminal repeats (LTR). Particularly striking was that parts of the virus responsible for binding to the cell receptor looked more like those of an exogenous virus as opposed to the more endogenous form possessed by KoRV-A. Indeed, when they looked at receptor usage, KoRV-B used a different receptor to KoRV-A and GALV.

Mother to Joey transmission: Joeys only become infected with KoRV-B when the dam is infected, even if the sire is positive, implying the virus is transmissible rather than inherited. (Xu et al 2013)

Further evidence of the infectious nature of KoRV-B came from the observation of infected (or not) joeys born to infected (or not) parents in a family at Los Angeles zoo. A positive joey was only born when the mother was positive; it was possible for a joey to be born negative for KoRV-B even if the father was positive for KoRV-B (as long as the mother is negative).

Koalas would appear in a bad way. However, endogenous retroviruses aren't necessarily harmful. On the contrary, some may be beneficial. A prime example is the JSRVs. The presence of endogenous JSRVs results in so-called 'late restriction'. Interference of exogenous JSRV replication by the presence of endogenous JSRVs is ultimately beneficial for the sheep.

Endogenous JSRVs: a variety of genomic arrangements of JSRVs found in the sheep genome. (Arnaud et al 2007)

Inevitably, as the sheep genome is targeted in further rounds of infection by exogenous JSRVs, a tug of war develops such that a balance exits between the late restriction imparted by endogenous JSRV(s) and the exogenous JSRV. The sheep genome has been invaded multiple times by JSRV, to the extent that the domestication of sheep can be traced based upon which endogenous JSRVs are present in the genome of a particular sheep breed (Chessa et al 2009).
Whether it's too late for something similar with the koalas, time will tell.

Wenqin Xu, Cynthia K. Stadler, Kristen Gorman, Nathaniel Jensen, David Kim, HaoQiang Zheng, Shaohua Tang,, & William M. Switzer, Geoffrey W. Pye, Maribeth V. Eiden (2013). An exogenous retrovirus isolated from koalas with malignant neoplasias in a US zoo Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1304704110

Arnaud F, Caporale M, Varela M, Biek R, Chessa B, Alberti A, Golder M, Mura M, Zhang YP, Yu L, Pereira F, Demartini JC, Leymaster K, Spencer TE, & Palmarini M (2007). A paradigm for virus-host coevolution: sequential counter-adaptations between endogenous and exogenous retroviruses. PLoS pathogens, 3 (11) PMID: 17997604

Chessa B, Pereira F, Arnaud F, Amorim A, Goyache F, Mainland I, Kao RR, Pemberton JM, Beraldi D, Stear MJ, Alberti A, Pittau M, Iannuzzi L, Banabazi MH, Kazwala RR, Zhang YP, Arranz JJ, Ali BA, Wang Z, Uzun M, Dione MM, Olsaker I, Holm LE, Saarma U, Ahmad S, Marzanov N, Eythorsdottir E, Holland MJ, Ajmone-Marsan P, Bruford MW, Kantanen J, Spencer TE, & Palmarini M (2009). Revealing the history of sheep domestication using retrovirus integrations. Science (New York, N.Y.), 324 (5926), 532-6 PMID: 19390051

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