The overall theme of my research is to understand the interactions between viruses and our body. This includes how viruses cause disease and how our immune system combats viruses. It also includes the biology of vaccines.

• Herpes simplex virus (and herpesviruses in general), especially latency
• Antigen presentation, especially to CD8⁺ T cells
• Vaccinia virus as a vaccine vector
  
• Vaccinia virus (and poxviruses in general)

David Tscharke began his research career at the University of Adelaide and IMVS in Adelaide, studying interactions between the immune system and herpes simplex virus (HSV, the cause of cold sores). After gaining his PhD he worked in postdoctoral positions at Oxford University and then Imperial College London in the UK, working on projects related to viral pathogenesis and vaccine design. Following this, he moved to the US National Institutes of Health (Bethesda, MD) where he focused on understanding how the immune system recognises viruses and vaccines. He then returned to Australia, working first at QIMR in Brisbane, before starting his own lab and taking on undergraduate teaching in the former department of Biochemistry and Molecular Biology at the ANU in 2006. Since then he has received a Young Tall Poppy Award and has held an NHMRC Career Development Award and ARC Future Fellowship. In 2016 he moved his laboratory across campus to the John Curtin School of Medical Research (JCSMR) and took up an NHMRC Senior Research Fellowship. He was Head of the Department of Immunology and Infectious Diseases at JCSMR from mid-2017 to mid-2023 and has been an NHMRC Leadership Fellow since 2022. Throughout his career he has had the benefit of working with excellent mentors, generous collaborators and brilliant students. His current research combines all the themes he has developed throughout his career, from understanding the dormant phase of infection with HSV to gaining new insight into the way our immune system recognises and responds to viruses and vaccines.

Understanding the role of ongoing viral activity in herpes simplex virus latency
Herpes simplex viruses (HSV) type 1 and 2 are highly prevalent pathogens that cause substantial morbidity and occasional deaths. Recurrent ocular infections can lead to blindness and increasing genital HSV-1 infections and shedding during childbirth are a growing risk to neonates. These two important clinical situations highlight the importance of understanding HSV latency and the significance of any therapy that could inhibit the reactivation of the virus. Despite this importance, the mechanisms controlling the HSV latency remain poorly understood. In part this is due to an understanding of latent infection that emphasises the importance of the restriction of viral gene expression. Our finding that multiple HSV genes can be expressed during latency and that neurons are responding, suggests a new paradigm and hope for therapeutic interventions that boost the ability of the host to maintain latent infection. The way forward is to 1) further explore this new paradigm in our highly tractable mouse model, 2) to translate it to human neurons and then 3) identify and test host pathways that restrict HSV infection. This approach forms the aims of this proposal. Ultimately the pathways we identify might yield targets for future therapies that aim to keep HSV latency truly silent.

Recognition of virus-infected cells by CD8⁺ T cells
Hypothesis: A systematic approach to immunopeptidomes and their immunogenicity will provide insights for anti-viral immunity, vaccine design and mechanisms of autoimmunity.
Viral infections constitute a significant health burden world-wide and a better understanding of anti-viral immunity is required to improve vaccines. The other side of effective immunity is autoimmunity, and there is a long history of association between infection and autoimmune diseases. In each case a clearer understanding of the interaction between pathogens and the immune system is needed. One of the most vital interfaces between host and virus is the display of virus peptides in the context of MHC I on infected cells and the response of CD8+ T cells. Despite this clear significance, our understanding of the full range of peptides that are presented (or immunopeptidomes) and how they shape the specificity
of anti-viral CD8+ T cell responses remains highly fragmented. We are exploring these issues using vaccinia virus, arguably the most successful human vaccine and also a virus for which we have well characterised models in mice, enabling the quantitative study of immunopeptidomes and responding T cells. Using this model we are establishing and comparing detailed immunopeptidomes for vaccinia virus on cell lines, primary cells and cells from infected mice. Next we are determining what fraction of an immunopeptidome elicits CD8⁺ T cell responses. We are also investigating whether central tolerance mechanisms narrow the range of epitopes targeted by anti-viral immunity and whether immunodomination and competition amongst peptides for presentation reduces immunogenicity of some epitopes.

Equiries are welcome from potential honours or PhD students with an inteterst in topics at the interface between virology and immunology, and especially antigen presentation to CD8⁺ T cells. A variety of projects are available, from the molecular virology of HSV latency to quantitative studies of antigen presentation on class I MHC. Prospective students are encouraged to read our recent publications and contact David if there is a good fit between your interest and our areas of research.