School of Animal and Veterinary Sciences, University of Adelaide

Dr Natasha Speight (BSc BVMS PhD) is a senior lecturer at the School of Animal and Veterinary Sciences, University of Adelaide. Natasha has led koala health and disease research in South Australia for over 15 years, with broad interests in both infectious and non-infectious diseases. Recent topics of research have included Chlamydia infection, kidney disease, thyroid disease, blood reference intervals, and bushfire injury outcomes. Natasha has supervised two PhD student projects focussed on koala retrovirus, with the overarching aims of determining prevalence and pathology of infection, including cancers, in South Australian koalas. This research has led to 10 journal publications on koala retrovirus, several as part of collaborative projects. Natasha continues to be interested in the transmission and pathogenesis of koala retrovirus, and how this can be applied to the conservation and management of populations.

Abstract

Koala retrovirus in southern koalas

Natasha Speight¹

¹ School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy, South Australia.

Following an expansion of research on endogenous koala retrovirus (KoRV) in northern Australian koalas, our research aimed to investigate KoRV infection of southern koalas, particularly prevalence, associated pathology, and molecular characteristics. We sampled a total of 245 wild koalas from two large and geographically distinct South Australian populations to determine KoRV prevalence, and examined 92 koalas at postmortem examination for pathology and histopathology associated with infection. Following this, samples from 216 koalas were used for characterisation of the KoRV provirus genes, and subsequently the KoRV expression profile, to improve molecular diagnosis and better understand transmission dynamics. We determined a prevalence of 42% of KoRV in the Kangaroo Island koala population, and 65% in the Mount Lofty Ranges population. KoRV-A and not KoRV-B were detected, and proviral loads were low. Of the 92 post-mortem cases, four koalas were found to have lymphoma, and these had high proviral loads. All proviral genes (gag1, gag2, pol, env1, env 2) were found to be present in 89/216 koalas (41%), however the KoRV expression profile in the central region (gag2, pol, env1) for three of these positive koalas was fragmented compared to two positive koalas with lymphoma. Koalas that were negative for central KoRV proviral genes showed expression of gag 1 and terminal regions. The lower prevalence of KoRV, lower proviral loads in positive koalas, and incomplete expression profile unless lymphomic, point to predominantly exogenous transmission of KoRV in southern koalas, but the presence of retroviral gene segments in KoRV-negative koalas suggests an endogenisation event.

Section of Infections of the Nervous System, National Institute of Neurological | Disorders and Stroke, National Institutes of Health, Bethesda, Maryland USA

Avindra (Avi) Nath is the Clinical Director of the National Institute of Neurological Disorders and Stroke (NINDS) at NIH, where he is also Chief of the Section of Infections of the Nervous System, Director of the Translational Center for Neurological Sciences. He started his research career studying the neuropathogenesis of HIV infection and has applied those principles to study the neuropathogenesis of endogenous retroviruses. His laboratory discovered the expression of HML-2 in ALS and glioblastoma which is now a major focus of research in his lab. His laboratory has also studied the neuropathogenesis of emerging infections such as Ebola, Zika virus and SARS-CoV-2 and conducts research on patients with undiagnosed neuroinflammatory disorders. The common underlying theme is to study mechanisms of viral persistence in the brain and develop novel therapeutic approaches. He is the past President and the recipient of the Pioneer award from the International Society of NeuroVirology and received an award for scientific achievements by the World Federation of Neurology. He is an elected member of the Association of American Physicians, the National Academy of Medicine, a fellow of AAAS and a previous Board member of the American Neurological Association. In 2024, TIME magazine named him amongst the 100 most influential people in health.

Abstract

Endogenous Retroviruses in Pathophysiology and as Therapeutic Targets in Amyotrophic Lateral Sclerosis

Several retroviruses have been implicated in the pathophysiology of motor neuron disease or amyotrophic lateral sclerosis (ALS)-like syndromes. This includes murine leukemia virus, HIV and HTLV-1. We and others have found that several loci within the human chromosome for an endogenous retrovirus, HML-2, get activated and cause toxicity of motor neurons resulting in the phenotype of ALS. These viruses highly mutated but can form immature viral particles. They are critical in early embryonic development but are silenced in the healthy adult brain. The toxicity is mediated by the envelope protein of the virus via a multitude of mechanisms. This includes aggregation of TDP-43, translocation of the signal peptide to the nucleolus, interactions with CD98HC on neurons which is also the receptor of the virus and dysregulation of immune responses to the virus. Other proteins encoded by the virus are also expressed in ALS, however, their role in the pathophysiology of the disease is not fully understood. None the less, the expression of these proteins provides several new therapeutic targets. This includes development of vaccines and therapeutic antibodies to neutralize the envelope protein, shRNA to decrease its expression, and new compounds that would target the reverse transcriptase, protease, integrase or capsid of the virus. Pilot studies have been conducted using combination antiretroviral drugs in ALS. They have identified a subgroup of individuals in whom the viral load decreases with treatment and rebounds following withdrawal of the drugs. The clinical relevance of these observations needs to be confirmed in larger studies.

Department of Biology, University of Oxford

Emma is a paleovirologist studying the evolution, transmission and co-option of viruses in vertebrates. She completed her undergraduate studies and PhD at the University of New South Wales in Sydney before moving to the UK to work as a postdoctoral researcher at the University of Oxford. Traditionally trained as a molecular virologist, she has a background in wet-lab techniques, working to develop broad-spectrum antiviral candidates, monitor circulating viruses from clinical and environmental samples, and contribute to the NSW Health COVID-19 response through wastewater analysis of SARS-CoV-2. During her PhD, Emma transitioned to bioinformatic research and now exclusively works with computers, developing methods and analyses to understand overarching trends and patterns of virus evolution.

Abstract

Endogenous retroviruses as viral fossils: detection methods and evolutionary insights

Emma F Harding¹, Laura Munoz-Baena¹, Aris Katzourakis¹,

¹Department of Biology, University of Oxford

Retroviridae is an important viral family that contains many mammalian pathogens and has a long history of co-evolution with vertebrates. The obligate integration of retroviruses into host DNA during infection leads to endogenous retroviruses (ERVs), which can be passed on to progeny if integrated in a germline cell. These elements act as molecular “fossils”, providing insights into evolutionary trends over millions of years. ERV classification is a difficult endeavour, with modern retroviruses representing only a fraction of their historical diversity. In addition, modern retroviruses are often the product of multiple historical recombination and transmission events, making tracing their evolutionary path challenging. We created a pipeline to detect ERVs based on sequence similarity to retroviral proteins using DIAMOND, reconstruct the ancestral proteins using Genewise and classify them with custom developed HMMs. We then systematically search and evaluate degradation of LTRs to date ERVs. Finally, we use MMseqs to cluster the reconstructed sequences, calculate k-mer distances and construct networks to visualise their relationships and connections. Collecting data from 4,155 vertebrate genomes, we identify discrepancies in the types and rate of retroviral integration in different host orders, indicating the differential burdens that retroviral infections have on species over time. We also identify ERVs from recently circulating retroviruses to understand the transmission dynamics influencing the modern global retrovirome. Finally, we explore the origins of retroviral genera, expanding our understanding of the evolutionary patterns that shape this viral family.