Koala (Phascolarctos cinereus) retrovirus (KoRV) is a gammaretrovirus, related to feline leukaemia virus (FeLV) and murine leukaemia virus (MuLV) and, more closely, gibbon ape leukaemia virus (GALV) (Alfano et al. 2016).
The virus was first described by Hanger et al. (2000), but the existence of a retrovirus in koalas had been suspected for several years because of the relatively high rates of lymphoid neoplasia seen in zoo-housed (Hanger et al.
2000) and free- ranging koalas (Canfield 1987; Spencer and Canfield 1996), the detection of type C retrovirus-like particles budding from leukaemic cells of a koala by transmission electron microscopy (TEM) (Canfield et al. 1988) and the discovery of sequence homologous to the pol region of MuLV and GALV in the DNA of a koala (Martin et al. 1999). KoRV is of interest in the clinical and population management of koalas, because of the growing evidence of its potential to cause immunosuppressive and neoplastic disease. It is also of significant interest to the study of retroviral evolution, because aspects of its behaviour suggest it may be in the process of endogenising (becoming incorporated into the koala germ line), as well as to biomedical researchers for its potential as a vector for genetic modification. It has, therefore, been the subject of several reviews (Denner and Young 2013; Xu and Eiden 2015; Kinney and Pye 2016; Greenwood et al. 2018) and associated research is evolving rapidly, with the latest research and consensus on management implications presented in Proceedings of the Second Koala Retrovirus Workshop (Alquezar-Planas et al. 2023).It appears most likely that KoRV originated in a native Australian rodent, the grassland melomys (Melomys bur- toni), but connections between M. burtoni and KoRV’s closest relative, GALV, are unclear, which suggests other species could also be involved (Greenwood et al. 2018). In M. burtoni, an apparently ancestral virus (MbRV) was discovered and detected in all animals tested, but no other candidate has been detected in the 42 Australian rodent, bat, feral vertebrate and marsupial species screened to date (Simmons et al.
2014). A similar, more recent spillover of KoRV’s closest relative, the exogenous, pathogenic GALV, appears to have occurred from rodents in South-East Asia in the mid-late 60s, though there have been no new reports of infection by that virus since 1978 (Brown and Tarlinton 2016). Studies of KoRV in museum koala skins from the late 19th and early 20th centuries (Avila-Arcos et al. 2013) found that KoRV was already ubiquitous in northern Australia by the late 19th century, and sequence divergence between the 5' and 3' long-terminal repeat (LTR) regions indicates that KoRV entered the koala genome sometime within the past 50 000 yr (Ishida et al. 2015), which is the most recent date for any known endogenous retrovirus (ERV).There is no strict definition of ERVs, but integration into the germ cells and vertical inheritance from one generation to the next are considered to be essential characteristics (Gifford and Tristem 2003). ERVs have been found in all vertebrates studied, as well as in some invertebrates. They are often millions of years old and the phylogenic trees of ERVs frequently mirror the phylogenic trees of the species involved, indicating co-evolution. Over this time, ERVs often become fixed in the genome (Gifford and Tristem 2003) and are often heavily methylated and repressed by epigenetic mechanisms (Schulz et al. 2006). Mutations generally accumulate over time and many ERVs degrade into ‘junk DNA' (Gifford and Tristem 2003). Approximately 8% of the human genome is made up of ERVs (Belshaw et al. 2004). In contrast, exogenous retroviruses are spread horizontally and are integrated into the somatic cells but not the germ cells. These viruses are frequently pathogenic.
One of the most dynamic areas of KoRV research in recent years has been the discovery and characterisation of several KoRV subtypes, or variants, which has greatly expanded our understanding of KoRV phylogeny, behaviour and potential for pathogenesis. Following some initial taxonomic confusion, our current understanding is based on deep sequencing of the hypervariable region A of the env gene (Chappell et al.
2017), which is involved in retroviral receptor determination and recognition. The 108 distinct env gene sequences obtained in that study from genomic DNA and plasma viral RNA of 18 koalas of south-east Qld origin indicated that KoRV comprises a family of related retroviruses that fall into three main clades: KoRV A, KoRV B/J (Shimode et al. 2014) and a highly diverse polyphyletic subtype KoRV D, within which lie two previously described subtypes named KoRV C (Shimode et al. 2014) and E (Xu and Eiden 2015), and novel subtypes KoRV F, G, H, I and K-M. Subtypes D and E have been described as defective forms in one koala, but it is unclear whether this is the exception or the rule for those subtypes or the clade (Hobbs et al. 2017). KoRV A displays limited diversity, consistent with a relatively inactive ERV, and the diversity of the remaining subtypes is consistent with the dynamic evolution expected in an active, exogenous virus. Given the small and geographically restricted sample sets included in studies to date, it seems reasonable to expect that additional subtypes exist.1.