Koala retrovirus diversity, transmissibility, and disease associations

Abstract

Background Koalas are infected with the koala retrovirus (KoRV) that exists as exogenous or endogenous viruses. KoRV is genetically diverse with co-infection with up to ten envelope subtypes (A-J) possible; KoRV-A is the prototype endogenous form. KoRV-B, first found in a small number of koalas with an increased leukemia prevalence at one US zoo, has been associated with other cancers and increased chlamydial disease. To better understand the molecular epidemiology of KoRV variants and the effect of increased viral loads (VLs) on transmissibility and pathogenicity we developed subtype-specific quantitative PCR (qPCR) assays and tested blood and tissue samples from koalas at US zoos (n = 78), two Australian zoos (n = 27) and wild-caught (n = 21) in Australia. We analyzed PCR results with available clinical, demographic, and pedigree data. Results All koalas were KoRV-A-infected. A small number of koalas (10.3%) at one US zoo were also infected with non-A subtypes, while a higher non-A subtype prevalence (59.3%) was found in koalas at Australian zoos. Wild koalas from one location were only infected with KoRV-A. We observed a significant association of infection and plasma VLs of non-A subtypes in koalas that died of leukemia/lymphoma and other neoplasias and report cancer diagnoses in KoRV-A-positive animals. Infection and VLs of non-A subtypes was not associated with age or sex. Transmission of non-A subtypes occurred from dam-to-offspring and likely following adult-to-adult contact, but associations with contact type were not evaluated. Brief antiretroviral treatment of one leukemic koala infected with high plasma levels of KoRV-A, -B, and -F did not affect VL or disease progression. Conclusions Our results show a significant association of non-A KoRV infection and plasma VLs with leukemia and other cancers. Although we confirm dam-to-offspring transmission of these variants, we also show other routes are possible. Our validated qPCR assays will be useful to further understand KoRV epidemiology and its zoonotic transmission potential for humans exposed to koalas because KoRV can infect human cells.

Retroviral integrations contribute to elevated host cancer rates during germline invasion

“…We find that northern koalas carry a high mutational burden from a rapid expansion and accumulation of endogenous KoRV integrations in the population. All koalas in the northern population likely carry similar numbers of KoRV-A proviruses 67 with some proviral IS possibly conferring a higher cancer risk than others. It is also clear that this germline mutational load is compounded in individual koalas by substantial accumulation of somatic integrations.…”

Differential and defective transcription of koala retrovirus indicates the complexity of host and virus evolution

“…KoRV-A infections in southern animals may represent genuine exogenous (infectious) virus as these are in many cases also present at less than one copy per genome equivalent [5]. The non-A variants may also represent genuine exogenous (infectious) virus in both northern and southern animals, circulating independently with these present as low copy number/somatic insertions [22, 33, 34], not detected in all animals [24, 25, 29, 35–37] and display a pattern of detection in family groupings consistent with a maternally transmitted infection [28, 35, 37, 38]. Some caution is necessary in interpreting this however as phylogenetic analysis of the envelope variants from a variety of sequencing studies do not clearly indicate chains of transmission [29, 31, 36].…”

CD4, CD8b, and Cytokines Expression Profiles in Peripheral Blood Mononuclear Cells Infected with Different Subtypes of KoRV from Koalas (Phascolarctos cinereus) in a Japanese Zoo

“…The endogenized form of KoRV is KoRV-A, and nine other subtypes (KoRV-B to J) have been identified to date [ 17 ]. Of these subtypes, KoRV-A and KoRV-B have been characterized to the greatest extent [ 18 , 19 ].…”