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Walter + Eliza Hall Institute of Medical Research
Investigating clinical therapeutics to kill infected cells and promote HIV clearance Philip Arandjelovic Infection and Immunity Division Walter + Eliza Hall Institute of Medical Research
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Conflict of Interest The Walter and Eliza Hall Institute of Medical Research stands to gain financially from the compound known as ABT-199 (Venetoclax).
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The Balance of Life and Death
Pro-apoptotic Pro-survival
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The Balance of Life and Death
Pro-survival Pro-apoptotic
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Intrinsic Apoptosis Cytoplasm Pro-survival Bcl-2 family BAX BAX/BAK
oligomerisation Nucleus Caspase-9 Caspase-3/7 Apoptosome
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Intrinsic Apoptosis Cellular stress Cytoplasm
Pro-survival Bcl-2 family BAX Pro-apoptotic BH3-only Bcl-2 Bcl-xL Bcl-w Mcl-1 Nucleus A1 Caspase-9 Caspase-3/7 Apoptosome
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Intrinsic Apoptosis Cellular stress Cytoplasm
Pro-survival Bcl-2 family BAX Bcl-2 Pro-apoptotic BH3-mimetics Bcl-xL Bcl-w Mcl-1 Nucleus A1 Caspase-9 Caspase-3/7 Apoptosome
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BH3-mimetics exhibit differential specificity for Bcl-2 family members
ABT-199 Bcl-2 Bcl-xL Bcl-w Mcl-1 A1
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HIV exploits the longevity of memory CD4+ T cells to maintain a reservoir
Pro-survival Pro-apoptotic
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HIV exploits the longevity of memory CD4+ T cells to maintain a reservoir
ABT-199 Pro-survival Pro-apoptotic
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A Balance of Life and Death
The intrinsic apoptotic pathway can be targeted to induce clearance of the HIV reservoir in vivo Pro-survival Pro-apoptotic
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In Vivo Timeline: Viral Rebound
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Untreated mice rebound within one week of ART interruption
Weeks post-infection Error bars = SEM, n = 6 animals per group
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Untreated mice rebound within one week of ART interruption
Weeks post-infection Error bars = SEM, n = 6 animals per group
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Untreated mice rebound within one week of ART interruption
ABT-199 ABT-199 Error bars = SEM, n = 6 animals per group
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ABT-199 delays rebound by up to two weeks post therapy interruption
Error bars = SEM, n = 6 animals per group
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ABT-199 delays rebound by up to two weeks post therapy interruption
Error bars = SEM, n = 6 animals per group
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In Vivo Timeline: assessing integrated HIV DNA
Humanized mouse ABT-199 ABT-199 ABT-199 Time (weeks) 3 11 12 13 14 15 Initiate ART I.P HIV infection FTC, TDF, RAL, RILP Quad ART -Integrate DNA -CA RNA -Immunophenotype
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ABT-199 kills lymphocyte populations in lymph nodes of humanized mice
Spleen Bone Marrow Error bars = SEM, n = 3 animals per group
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ABT-199 kills lymphocyte populations in lymph nodes of humanized mice
Blood Error bars = SEM, n = 3 animals per group
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Cell-associated HIV RNA is detectable in aviremic humanized mice
Error bars = SEM, n = 3 animals per group
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Vendergeeten et al., J Virol, 2014
Error bars = SEM, n = 3 animals per group Vendergeeten et al., J Virol, 2014
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Mice treated with ABT-199 harbour less integrated HIV DNA
Error bars = SEM, n = 3 animals per group Vendergeeten et al., J Virol, 2014
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Summary and Future Directions
ABT-199 delays viral rebound by up to 2 weeks in a humanized mouse model of latent HIV infection. Lymph nodes are highly susceptible to ABT-199 killing of key populations, including Central and Effector Memory CD4+ T cells. ABT-199 diminishes levels of integrated HIV DNA in spleen and lymph nodes.
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Summary and Future Directions
Experimenting with treatment regimens to extend time-to-rebound. ABT-199 Bcl-2 Bcl-xL Bcl-w Mcl-1 A1 ?
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Acknowledgements Pellegrini Lab Infection & Immunity Division
Marc Pellegrini Cody Allison Simon Preston James Cooney Samar Ojaimi Michael Stutz Greg Ebert Jesse Toe Marcel Doerflinger Zina Valaydon Wasan Forsyth Liana Mackiewicz Mel Hobbs Yisheng Zhang Michelle Clark Sam Finlayson Infection & Immunity Division Sara Erickson Joan Curtis Stella Kyvetos PhD Committee Gabrielle Belz Peter Revill Bioservices Merle Dayton Shauna Ross Angela Milligan Lewin/Cameron Lab – The Peter Doherty Institute Ajantha Rhodes The University of Melbourne Stephen Kent
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