Why we should ‘shock and kill’

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Presentation transcript:

Why we should ‘shock and kill’ Professor Sharon R Lewin, FRACP, PhD, FAHMS Director, Doherty Institute, The University of Melbourne and Royal Melbourne Hospital IAS Community Workshop of HIV Cure, Amsterdam, July 2018

Some definitions Shock and kill Block and lock

Eliminate viral rebound off ART The overall goal Safe Time limited Cheap Accessible Effective in all clades Eliminate viral rebound off ART through Reducing the replication competent reservoir

Shock and kill: a two step strategy Immune mediated killing or Pro-apoptotic drugs Shock Latency reversing agent Productive infection Cell death Latent infection

We have many drugs that can ‘shock’ None are HIV specific None are as potent as T-cell activation Unclear if virus is coming from all cells or just a few Still need better LRAs dCA Kim, Anderson and Lewin. Cell Host Microbe 2018

What about the kill? Vaccines Immune check point blockade CAR T-cells Antibodies BITEs DARTs bNAbs

What happens when we combine shock + kill? Romedepsin Vacc 4x REDUC Lancet HIV N=17 = + No change in DNA shock kill Romedespin ChAd/MVA BCN02 CROI2018 N=15 + = Viral rebound (half) Vorinostat ChAd/MVA HIVcons RIVER AIDS 2018 N=60 = No change in DNA + TLR7 PGT121 bNAB + = REMISSION (50%) monkeys

Kill compounds Shock + HIV proteins/RNA Latent infection Cell death OX40/SIRC Kuo, Immunity 2018 Cummins J Virol 2016 Wong Nat Med 2016 Cummins AIDS 2018 Kim AIDS2018 Munoz-Arias AIDS2018 survival Cell death

What are the challenges for shock and kill? Need more potent, less toxic and more specific agents that shock. Combinations of shock agents coming Unclear if targeting all infected cells will be possible, especially tissue Could activating virus have adverse effects on immune activation, brain reservoirs? No evidence in 10+ trials Immune escape might be a problem for immune mediated killing but not kill compounds This is just about reducing the reservoir - will still need long term immune control

What will be better? Safe Time limited Cheap Accessible Shock and kill Block and lock Safe Time limited Cheap Accessible Effective in all clades Induce remission off ART