Induction of neutralizing antibody response against koala retrovirus (KoRV) and reduction in viral load in koalas following vaccination with recombinant KoRV envelope protein

Olagoke, Olusola; Miller, Diane; Hemmatzadeh, Farhid; Stephenson, Tamsyn; Fabijan, Jessica; Hütt, Pirje; Finch, S; Speight, Natasha; Timms, Peter

doi:10.1038/s41541-018-0066-4

Cited by 20 publications

(63 citation statements)

References 42 publications

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“…Immune responses to the virus have been shown to vary between these populations in other studies 33,34 . QLD animals may become immunologically tolerant to the virus through in-utero expression of endogenous viral genes, resulting in an inability to respond effectively to infection by exogenous virus in later life, leading to high viral loads.…”

Section: Discussionmentioning

confidence: 90%

“…showing no detectable antibodies 35 while others reported that Qld koalas in fact produced antibodies to multiple KoRV antigens 34 . In contrast, it has been suggested that SA animals might be infected only with an exogenous virus and as such are able to mount an immune response to the virus, as shown in a study in which both KoRV positive and negative koalas developed KoRV antibodies upon vaccination 34 . Conversely, it is also possible that SA koalas might possess partial replication-defective endogenous KoRV sequences, which provide protection against exogenous virus replication.…”

Section: Discussionmentioning

confidence: 97%

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Koala retrovirus viral load and disease burden in distinct northern and southern koala populations

Sarker

Fabijan

Owen

et al. 2020

Sci Rep

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Koala retrovirus (KoRV) displays features of both an endogenous and exogenous virus and is linked to neoplasia and immunosuppression in koalas. This study explores the apparent differences in the nature and impact of KoRV infection between geographically and genetically separated "northern" and "southern" koala populations, by investigating the disease status, completeness of the KoRV genome and the proviral (DNA) and viral (RNA) loads of 71 northern and 97 southern koalas. All northern animals were positive for all KoRV genes (gag, pro-pol and env) in both DNA and RNA forms, whereas many southern animals were missing one or more KoRV genes. There was a significant relationship between the completeness of the KoRV genome and clinical status in this population. The proviral and viral loads of the northern population were significantly higher than those of the southern population (P < 0.0001), and many provirus-positive southern animals failed to express any detectable KoRV RNA. Across both populations there was a positive association between proviral load and neoplasia (p = 0.009). Potential reasons for the differences in the nature of KoRV infection between the two populations are discussed. Koala retrovirus (KoRV) was first identified in tissues from a leukemic koala in 1988 1 and the full genome sequence was published in 2000 2. This is a unique endogenous retrovirus which is also capable of being transmitted horizontally 3. It is thought that KoRV plays a role in the pathogenesis of lymphoid neoplasia as well as causing immunosuppression, making koalas more susceptible to developing overt chlamydial disease 4 , which is a major threat to koala populations. However while there appears to be a strong association between KoRV infection and these diseases in koalas, there is currently little if any published data proving a causal link 3,5,6. Anecdotally, there are differences in disease prevalence between koala populations in northern and southern Australia. The prevalence of lymphoid neoplasia is high in northern koalas 7 compared to southern koalas where lymphosarcoma has only recently been reported 8. The prevalence of Chlamydia pecorum infection and overt chlamydial disease is also high in northern koalas in comparison to southern populations, with chlamydial disease reported in 52% of more than 20,000 koala admissions to wildlife hospitals in South East Queensland (SE QLD) 9. In contrast, a recent necropsy study in South Australia (SA) reported only 21% of koalas with clinically overt disease 10. Conversely, SA kocalas have a higher prevalence of oxalate nephrosis than QLD koalas, with 55% of SA koalas demonstrating renal dysfunction due to oxalate nephrosis 11. These differences in disease prevalence may be the result of genetic differences between northern southern koala populations 12. Animals in the southern part of the range (the states of Victoria, South Australia [SA] and southern New South Wales [NSW]) have undergone a severe genetic bottleneck as a result of hunting pressures in the late 1800's. Thes...

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 97%

Koala retrovirus viral load and disease burden in distinct northern and southern koala populations

Sarker

Fabijan

Owen

et al. 2020

Sci Rep

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“…Total anti-KoRV IgG antibody levels were determined from serum as detailed in reference 37. Briefly, a near full-length recombinant KoRV-A env protein, minus the first 100 amino acids (inclusion of the first 100 amino acids prevented protein expression, therefore the recombinant protein begins at the RBD), was generated with a glutathione S-transferase (GST) tag for affinity purification (37). To compare the env protein conservation between KoRV subtypes, full-length env protein sequences were compared from KoRV-A (AF151794, BAN63359.1), KoRV-B (NC_021704.1, BAN63358.1), KoRV-C (ALX81658.1, BAN63361.1), KoRV-D (BAN63360.1), and KoRV-F (ANT96689.1).…”

Section: Methodsmentioning

confidence: 99%

“…Assay plates were coated with 1 g recombinant KoRV-A env protein overnight before washing and incubating with serially diluted serum samples. After additional washing, incubation with a sheep anti-koala IgG, further washing, incubation with a donkey anti-sheep horseradish peroxidase (HRP) IgG, final washing, and development with tetramethylbenzidine (TMB) liquid substrate (Sigma-Aldrich), optical density was read at 450 nm and endpoint titers (EPT) calculated (37).…”

Section: Methodsmentioning

confidence: 99%

Changes in Endogenous and Exogenous Koala Retrovirus Subtype Expression over Time Reflect Koala Health Outcomes

Chaban

Phillips

Olagoke

et al. 2019

J Virol

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Koala retrovirus (KoRV) is unique in that it exists as both an exogenous and actively endogenizing gamma retrovirus of koalas. While nine subtypes of KoRV have been recognized, focused study of these subtypes in koalas over time and with different health outcomes has been lacking. Therefore, in this study, three wild koala cohorts were established and monitored to examine KoRV proviral and expression data from koalas that either remained healthy over time, began healthy before developing chlamydial cystitis, or presented with chlamydial cystitis and were treated with antibiotics. Deep sequencing of the proviral KoRV envelope gene revealed KoRV-A, -B, -D, and -F to be the major subtypes in this population and allowed for subtype-specific assays to be created. Quantification of KoRV transcripts revealed that KoRV-D expression mirrored the total KoRV expression levels (106 copies/ml of plasma), with KoRV-A and KoRV-F expression being ∼10-fold less and KoRV-B expression being ∼100-fold less, when detected. Strikingly, there was significantly higher expression of KoRV-D in healthy koalas than in koalas that developed chlamydial cystitis, with healthy koalas expressing a major KoRV-D/minor KoRV-A profile, whereas koalas that developed cystitis had variable KoRV expression profiles. Total anti-KoRV IgG antibody levels were found not to correlate with the expression of total KoRV or any individual KoRV subtype. Finally, KoRV expression was consistent between systemic and mucosal body sites and during antibiotic treatment. Collectively, this gives a comprehensive picture of KoRV dynamics during several important koala health states. IMPORTANCE The long-term survival of the koala is under serious threat, with this iconic marsupial being declared “vulnerable” by the Australian Government and officially listed as a threatened species. KoRV is clearly contributing to the overall health status of koalas, and research into this virus has been lacking detailed study of the multiple subtypes at both the proviral and expressed viral levels over time. By designing new subtype-specific assays and following well-defined koala cohorts over time, this study has generated a new more complete picture of KoRV and its relationship to koala health outcomes in the wild. Only by building a comprehensive picture of KoRV during both koala health and disease can we bring meaningful koala health interventions into better focus.

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“…The presence of high levels of the various KoRV-subtypes in multiple tissues, including blood, and the endogenous source of KoRV that cannot be eliminated through breeding, all provide multiple exposure opportunities. While the stability of infectious KoRV in the environment is currently unknown, other gammaretroviruses like feline leukemia virus can survive for at least two days in culture medium but are inactivated after only a few hours if dried (43). Biosafety practices and procedures for persons handling koalas are important to prevent zoonotic exposures.…”

Section: Discussionmentioning

confidence: 99%

Koala Retrovirus Diversity, Transmissibility, and Disease Associations

Zheng¹,

Pan²,

Tang

et al. 2020

Preprint

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BackgroundKoalas 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.ResultsAll 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. ConclusionsOur 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.

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Induction of neutralizing antibody response against koala retrovirus (KoRV) and reduction in viral load in koalas following vaccination with recombinant KoRV envelope protein

Cited by 20 publications

References 42 publications

Koala retrovirus viral load and disease burden in distinct northern and southern koala populations

Koala retrovirus viral load and disease burden in distinct northern and southern koala populations

Changes in Endogenous and Exogenous Koala Retrovirus Subtype Expression over Time Reflect Koala Health Outcomes

Koala Retrovirus Diversity, Transmissibility, and Disease Associations

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