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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).