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Lab of Viral Zoonotics Jonathan Heeney Lab of Viral Zoonotics Understanding the Virome in One Health and Disease Zoonotic infections - acute vs persistent evolution of crossspecies transmissions Viral Zoonotics Jonathan Heeney DVM, DVSc(Path), PhD Professor of Comparative Pathology Department of Veterinary Medicine University of Cambridge viruses as symbionts viruses as pathogens The laboratory of Viral Zoonotics Examples Ebola/Marburg SARS MERS Niphavirus Hendravirus Avian flu (H5N1) West Nile Virus Japanese encephalitis virus Murray Valley encephalitis St Louis encephalitis virus yellow fever dengue fever Zika virus Chikungunya virus Hantavirus Lassa fever virus Argentinian HFV Bolivian HFV Rift valley fever Congo-Crimean HFV HIV-1 & 2 J. L. Heeney DVM, DVSc(Path), PhD Professor of Comparative Pathology Department of Veterinary Medicine University of Cambridge Zoonotic Viruses: Transient versus Host Adapted Viral Variants Wolfe et al Nature 2007 Wolfe et al, Nature 2007 HIV-1 / AIDS Ebola virus disease The scale of HIV-1 variation (compared to influenza virus) HIV: high genetic variability. Rapid diversity with the generation of 109 to 1010 virions/day, PLUS a high mutation rate of approx. 3 x 10-5 per nucleotide base changes per cycle of replication, PLUS recombinogenic properties of reverse transcriptase On the Origins of HIV and the AIDS epidemic why did HIV-1 go global? HIV- (vpu+ ) 1 SIVcp z guenon (vpu+ SIV ) guenon SIV HIV-2 …and not HIV-2? (vpu+ ) Mangabey (vpx+ SIV ) (vpx+ ) Out of Africa monkeys humans chimpanzees Human & Non-human primate Lentiviruses Out of Africa monkeys humans chimpanzees Human & Non-human primate Lentiviruses Out of Africa monkeys humans chimpanzees Human & Non-human primate Lentiviruses Out of Africa monkeys humans chimpanzees Human & Non-human primate Lentiviruses Out of Africa monkeys humans chimpanzees Human & Non-human primate Lentiviruses Out of Africa monkeys humans chimpanzees Human & Non-human primate Lentiviruses Host Restriction factors and Lentiviral Evolution Primate lentivirus Integration Target cell Shown is a Dendritic cell Host Restriction factors and Lentiviral Evolution Primate lentivirus Tetherin vpu APOBEC3G/F SAMHD1 Integration vpx Target cell Shown is a Dendritic cell vif gsn mus mon cpz rcm Bushmeat consumption & evolution of the HIV-1 pathogen © Ian Redmond © Karl Amman cpz © David Bygott HIV 2 © Karl Amman gsn mus mon rcm sm On the Origins of HIV and the AIDS epidemic why did HIV-1 go global? HIV- (vpu+ ) 1 SIVcp z guenon (vpu+ SIV ) guenon SIV HIV-2 …and not HIV-2? (vpu+ ) Mangabey (vpx+ SIV ) (vpx+ ) Will spill-over viruses evolve to become: Human Adapted Viral Variants like HIV-1? Wolfe et al Nature 2007 Wolfe et al, Nature 2007 ? Presentation title - edit in Header and Footer Molecular dating: 2014 Ebola outbreak 2014 Ebola outbreak = 8,600 deaths (22/01/15) (A) BEAST dating of the separation of the 2014 lineage from central African lineages [SL, Sierra Leone; GN, Guinea; DRC, Democratic Republic of Congo; time of most recent common ancestor (tMRCA), (B) September 2004; 95% highest posterior density (HPD), October 2002 to May 2006]. S K Gire et al. Science 2014;345:1369-1372 Ebola virus Unanswered questions: The animal reservoir, thought to be bats, is contested. The trigger of zoonotic spill-over to humans is unknown. With continued human to human transmissions will EBOV adapt humans giving a carrier state? What is the role of compromised hosts (humans) in EBOV outbreaks? The EBOLA outbreak of 2014 / 2015 What changed? Human carriers / persistence The EBOLA outbreak of 2014 / 2015 What changed? Human carriers / persistence -This was the longest most severe Ebola virus outbreak in history -More human to human transmissions than ever before (>28,000). -Expanded epidemic in large populations: Freetown, Conakry, Monrovia -Evidence of persistent infections in humans: carrier state?? Human reservoir? infected asymptomatic carriers? What is the role of the compromised host? Day 5 Day 7 Day 7 Day 7 Ebola Reservoirs: post-outbreak JL Heeney, Nature 527, 453–455 Nov. 2015 Heeney Nature 2015 Will spill-over viruses evolve to become: Human Adapted Viral Variants like HIV-1? Wolfe et al Nature 2007 Wolfe et al, Nature 2007 Did a Single Amino Acid Change Make Ebola Virus More Virulent? Bedford & Malik; Cell. Volume 167, Issue 4, 2016, 892–894 Did a Single Amino Acid Change Make Ebola Virus More Virulent? Bedford & Malik; Cell. Volume 167, Issue 4, 2016, 892–894 Figure 1. Evolutionary Course of the 2013–2016 Ebola EpidemicA time-resolved phylogenetic tree showing the evolutionary relationships among 1,261 Ebola viruses sampled during the 2013–2016 West African epidemic is depicted. Viruses (circles)... The Emergence of RNA viruses with Pandemic potential - Understanding molecular signatures associated with increased human to human transmission and viral virulence of emerging viruses are important for epidemic surveillance and preparedness - Epidemic potential is determined by a pathogens ability to overcome innate and adaptive immune defences of new hosts - Pandemic potential is determined by relative ineffective immune defenses to viruses which have adapted to replicate and spread rapidly with high morbidity and mortality in a large naïve populations. Acknowledgements The Lab of Viral Zoonotics Acknowledgements Viromics Genomics Immunopathology Immunity Eyal Maori, Marie Curie Fellow, Viral Integration, Viral Immunogenetics Amita Shortland, DVM, PhD (Cambridge), Murine viruses. David Seilly, Research Assistant protein chemistry and purification Sheryl Baptista, Research assistant, HIV vaccine evaluation, Arenaviruses. Samuel Stubbs, PhD student (MRC), Virome/Microbiome in CVID patients Paul Tonks, BSL-3 Lab & Flow sorting Facilities, Vaccine studies coordinator James Chettle, PhD Student (Wellcome Trust) Murine Norovirus Osama Eisa, MD, PhD candidate (IB), Microbiome and pathogen resistance. Zaria Gorvett, PhD candidate, Pathogenic origins of HIV-1 Chinedu Ugwu, DVA, Msc, PhD candidate, DCs and the Zoonotic origins of HIV-1 Sarah Beerbower, MPhil, PhD candidate, Viral activation and the GI microbiome Arden Dieker Viik, MPhil candidate, HIV-1 vaccine immune correlates Giacomo Gorini, MSc, PhD candidate (NIH), B-cell correlates of HIV vaccines. Simon Frost / Barbara Blacklaws / Laurence Tiley The Lab of Viral Zoonotics Acknowledgements Lab of Viral Zoonotics http://www.lvz.vet.cam.ac.uk http://www.lvz.vet.cam.ac.uk Lab of Viral Zoonotics Metavir 2: CL3 FACS containment lab Roux et al 2014 BMC Bioinformatics Acknowledgements “The Lab of Viral Zoonotics” Viromics Genomics Immunopathology Immunity Funding and Support The Wellcome Trust The Bill and Melinda Gates Foundation The National Institutes of Health The European Commission Kennel Club Trust The Newton Trust Draper & Heeney, Nature M-Rev 2010 EVAC Combining Viral Sequences B-Cell Epitopes T-Cell Epitopes Computational Analysis Synthetic Gene Technology To Create 60 Viral Envelopes Infection Assays Neutralisation Assays With Survivor and Vaccine Serum Neutralisation Assays With Monoclonal Antibodies Select Top 10 for Immunization DNA Prime Vector Boost Guinea Pigs Immunised and Challenged Select best Inserts For Human Vaccination Step 3- Immunizations envelope EVAC Insert best sequences into viral vectors Immunise guinea pigs with DNA prime and viral vector boosts Identify DIOS Ags that induce BNAbs across all Filoviruses EVAC Next step, Stream 2: Scale up GMP and phase I Human Clinical Trials Use the optimal antigen inserts for maximum breadth for human vaccine trials With a goal to create a vaccine capable of protecting a diverse population Phylogenic comparison of lentiviral genes Pol Env Nef - is EBOV circulating amongst wildlife in West Africa? - in which species can virus versus antibodies be found? - Is there evidence of other cross-species transmission events? - What are the risk factors that may trigger spill-over events? - Can predictive datasets of human transmission risks be generated from the West African epidemic and actual animal reservoirs? Animal reservoir: What are the infected WA animal reservoirs? Is this a transient epizootic or cyclic enzootic? First mission (Nov 2015) = survey and establishing logistics. - returned to the Guinean Prefect of Gueckedou where the West African Ebola epidemic originated 23 months ago. visited villages in neighbouring Prefects of Macenta and Kissidougou where Ebola first spread from Gueckedou. visited villages in these 3 Prefectures which had amongst the first cases and which were hardest hit in the epidemic. ☐ to disentangle the socio-anthropological issues and risk factors of transmission we visited communities in close geographic proximity to Ebola positive villages, (those which had no Ebola cases but shared the same ecosystems).