How to be the Perfect Host. and How they deal with us

Transcription

1 How to be the Perfect Host How we deal with viruses and How they deal with us

2 3 Parts Intro to viruses and immunity HCV making a vaccine HIV providing a cure

3 What is a virus? A piece of bad news wrapped up in protein Bacteria Generally grow outside the bd body s cells Viruses Always grow inside the body s cells

4 What is a virus? A piece of bad news wrapped up in protein

5 A typical virus Inner packing Outer shell Attachment protein Viral blueprint - may be DNA or RNA

6 How do viruses grow in cells? Cell

7 How do viruses grow in cells? Cell

8 How do viruses grow in cells? Cell

9 How do viruses grow in cells? Cell

10 How do viruses grow in cells? Cell Harnesses cell s machinery to multiply

11 How do viruses grow in cells? Cell

12 How do we defend ourselves? Imagine the body is like a large stately home (near Oxford). The individual cells in the body are like rooms in the home. A fantastic party is going gon The virus is not invited How do we stop the virus gatecrashing and spoiling the party?

13 The Host Moat West wing security Ballrooms East wing Dogs Driveway

14 The Host Moat Viruses need live cells to grow in - the skin acts like a moat Also known as The wall of death Viruses usually pick the easier route (up the drive) Or are parachuted in (by medics)

15 DOGS Fantastic Nose Great Ears BARK BITE

16 Innate Immunity Senses Danger Alerts security Can see off invaders single-handedly Interferon-lambda Interferons Dendritic cells

17 Calling security Dogs/innate immune system is fast and effective - but not that smart Adaptive immune system allows for SPECIFIC elimination of gatecrashers (but not guests). Each virus has its own dedicated security team

18 Security forces - white blood cells found in blood and also in lymph glands Security Alert

19 Security forces - white blood cells found in blood and also in lymph glands Security Alert Hand-to-hand killer (Killers) Logistics experts (Helpers) Cells making antibody

20 Killer T cells perform a room-room search Only investigate rooms where virus is present Try to clear out the room - failing that - destroy it Security Alert Antibodies soak up any virus found in corridors

21 Security in action A Killer T cell recognising and destroying a virusinfected target cell

22 HCV Global Epidemiology An estimated million people worldwide are infected

23

24 Immune response and clinical course Acute disease Persistent infection >80% T cell response Progressive disease mild disease Resolved infection <20%

25 The Host - improving security? Moat West wing Trained security Ballrooms East wing Dogs Very early brisk security operation

26 The immunogen the inside of HCV NS3-NS5B NS5B (NS = 1985 aa) Genotype 1, subtype 1b Most conserved HCV region Multiple epitopes Genetically inactivated NS5B (NSmut) NS3 Protease NS5Bmut AAG Met NS3 A NS4 NS5 B A B

27 Adenoviruses are shared by Humans and Chimpanzees - can be disabled genetically - chimps catch colds too! - can vector foreign antigens - have their own adenovirus strains - induce strong cellular immunity - little exposure of humans to these

28 HCV inside Chimp adenovirus vector Volunteers Safety Immune responses

29 TRAINED KILLER CELLS Identify individual cells with killing potential

30 Vaccine Phase I Science Trans Med 2012

31 T cell vaccines and HCV tik tricky opponent Magnitude Unpredictable ditbl Breadth Natural control Clever Mutable But reasons for optimism

32 Next steps Phase 2 How to trial Whom to trial in? Scale of trials? Options for those in trials? (Early treatment?) Incentives for those in trials? Funding for trials? When to trial too early/too late

33 Issue Basic Vaccine trials Works Phase II Ideal vaccine

34 Issue Basic Vaccine trials Works Improve Phase II Ideal vaccine

35 Issue Best of the bunch Basic scvcc Vaccine trials Works Improve Phase II Ideal vaccine

36 Is HIV Eradication Possible? Within host? Within populations?

37 Why ask the question? Vaccines don t work Vaccines won t work. HAART does work BUT Stops patients dying, reduces morbidity Is HAART the final answer? Is it realisitic to expect people to take life-long long therapy for an infectious disease?

38 HIV vs HCV HIV cannot be naturally eliminated like HCV Best we can currently do is reset the balance in favour of the host Therapy can suppress virus to undetectable levels and restore the immune system?can Early therapy have a bigger effect than later?

39 Result

40 Issues

41 Full life expectancy not restored Probabil lity of Su rvival by HAART Age, years Population controls HAART ( ) HAART ( ) Pre-HAART ( ) Danish HIV Cohort study n=3990; HIV neg controls n=379,872 Lohse et al., Ann Int Med 2007: 146: 87

42 Total projected annual AIDS resource requirements Billions of US dollars 35 Rapid scale-up (80% HAART coverage) Current trends (40% HAART coverage) AIDS treatment costs alone will account for half the the US foreign aid budget by 2016 Hecht et al., Health Affairs 2009; 28: 1591; Bongaarts et al., Science 2010; 328: 1359

43 Whom to treat?

44 Challenging model

45 Issues Is it feasible to roll out treatment on such a scale? Is it reasonable to do so? A vaccine might prevent transmissions but a therapy programme may work quicker? What about very aggressive therapy in patients to eradicate virus if possible? This is just a model could it be tested in a population for proof-of-concept?

46 Thanks Oxford Martin School Colleagues at Peter Medawar Building (Rodney Phillips, Ellie Barnes, John Frater) Wellcome Trust MRC/EU University of Oxford Oxford Biomedical Research Centre