Novel approaches for HIV cure

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Mervyn Goodwin
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1 Novel approaches for HIV cure Breach Symposium Guido Vanham 27 November 2015

2 Circulating virus Can HIV be eliminated or controlled without ART? ART Time HIV persists during ART 26/10/2015 2

3 HIV persists as a latent provirus under cart In untreated subjects: new viruses are produced by CD4 T cell activation In subjects under cart: cycle interrupted, but integrated provirus persists = source of rebound upon cart interruption! 26/10/2015 3

4 HIV persists as a latent provirus under cart In untreated subjects: new viruses are produced by CD4 T cell activation In subjects under cart: cycle interrupted, but integrated provirus persists If deeply latent no transcription no viral proteins/peptides = invisible to CD8 T cells 26/10/2015 4

5 Natural HIV control (Elite Controller or Elite Suppressor) EC/ES: low plasma viral load without treatment no or slow disease progression i.e. longterm non-progression (LTNP) Correlates? 26/10/2015 5

Natural HIV control (Elite Controller or Elite Suppressor) EC/ES: low plasma viral load without treatment no or slow disease progression i.e. longterm non-progression (LTNP) Correlates?

6 Natural HIV control (Elite Controller or Elite Suppressor) EC/ES: low plasma viral load without treatment no or slow disease progression i.e. longterm non-progression (LTNP) Correlates? - Low amount of proviral (integrated) DNA - High activity of CD8 T cells against infected CD4 T cells HIV progressor Elite controller HIV specific CD8 T cells HIV-infected CD4 T cells 26/10/2015 6

7 New concept of Functional Cure What? Induce Elite Controller status in patients with chronic infection How? - Improve CD8 T cell function = therapeutic vaccination - Render target cells resistant to HIV = gene therapy - Purge the latent proviral reservoir = anti-latency therapy 26/10/2015 7

8 HIV protective CD8 T cell responses? In non-treated HIV infected subjects: Kiepiela et al Nat Med 2007 CD8 T against Gag associated with lower viral load CD8 T against Env associated with higher viral load broadening and deepening of Gag responses could be beneficial 26/10/2015 8

9 DIVA trial: DC therapeutic vaccination Apheresis WBC Monocytes Differentiation HIV + subjects under cart Injection 4X Gag-expressing DC = vaccine Dendritic cells (DC) Electroporation with HIV-1 gag mrna Van Gulck et al. AIDS /10/2015 9

10 DIVA trial: induction of CD8 T cells against autologous infected CD4 T cells T1 V1 V2 T2 V3 V4 T3 T4 w -3 w 0 w 4 w 5 w 8 w 12 w 13 w 18 Suppression of vaccine-related HIV is induced in 3/5 patients Van Gulck et al. AIDS /10/

CD4 0 L m RNA Antigen: HIVACAT CD4 + Th support ac vated T cell survival and prolifera on CD40 CD40L induc on of DC

11 ihivarna principle: Intranodal vaccination with mrna encoding TriMix and HIVACAT in cart patients Activation signals: TriMix 1. CD4 0 L m RNA Antigen: HIVACAT CD4 + Th support ac vated T cell survival and prolifera on CD40 CD40L induc on of DC matura on Gag Pol Vif Nef 3. CD7 0 m RNA CD8 + CTL CD27 CD70 TLR4 LPS 2. catlr4 m RNA IN mrna! "#$%$&!"!! # $!%&' &() *+'! In situ loading of DC with antigenic and adjuvant mrna HIV-1 specific CD8 T-cell responses 26/10/

12 Possible strategies for Cure 1) Therapeutic vaccine: improve CD8 T cell function to suppress virus 2) Gene therapy: render target cells resistant to HIV infection OR excise integrated HIV from infected cells 3) Anti-Latency therapy: rescue AND PURGE the latent reservoir 26/10/

13 The Berlin patient The facts: Timothy Brown, HIV-infected with acute myeloid leukemia, treated with Total body irradiation: destruction of his own immune system Transplantation with hematopoietic stem cell (HSC), homozygous for the Δ32 mutation: no functional CCR5 26/10/

The Berlin patient The facts: Timothy Brown, HIV-infected with acute myeloid leukemia, treated with Total body irradiation: destruction of his own immune system Transplantation with

14 The Berlin patient The facts: Timothy Brown, HIV-infected with acute myeloid leukemia, treated with Total body irradiation: destruction of his own immune system Transplantation with hematopoietic stem cell (HSC) with the Δ32 mutation: no functional CCR5 After this treatment cart was not restarted and yet: No viral rebound High CD4 T cells Good health 26/10/

15 Genetic therapy deleting CCR5 Principle: Cell line can be transfected with so called Zinc finger nucleases, TALEN or CRISPR/Cas9 to delete CCR5 and render the cells resistant to HIV infection CCR5 26/10/

16 Future therapy: Deletion CCR5 in haematopoietic stem cells (HSC)? By CCR5 deletion 26/10/

17 Possible strategies for Cure 1) Therapeutic vaccine: improve CD8 T cell function to suppress virus 2) Gene therapy: render target cells resistant to HIV infection or excise integrated HIV 1) Anti-Latency therapy: rescue and PURGE the latent reservoir 26/10/

18 Anti-Latency treatment Principle: Some drugs (e.g. HDAC inhibitors) can activate the latent provirus virus production may kill infected cells 26/10/

19 Anti-Latency treatment Principle: Some drugs (e.g. HDAC inhibitors) can activate the latent provirus virus production may kills infected cells Or render them sensitive to CD8 T cells? 26/10/

20 Anti-Latency treatment Principle: Some drugs (e.g. HDAC inhibitors) can activate the latent provirus virus production may kill infected cells Or render them sensitive to CD8 T cells? Uninfected cells protected by cart 26/10/

21 Clinical trail of HDACi Romidepsin (under cart protection) Courtesy of O. Søgaard, Aarhus University 26/10/

22 Anti-Latency treatment Principle: Some drugs (e.g. HDAC inhibitors) can activate the latent provirus virus production may kill infected cells Or render them sensitive to CD8 T cells? uninfected cells protected by cart Problems: Non-specific activation of other genes how to make drugs more specific for HIV activation? 26/10/

23 Integration of various Cure approaches 1. Gene therapy: resistant HIV targets : CD4 T cells, DC, macrophages 2. Anti-latency: induces expression of viral epitopes for CD8 T cells 3. Therapeutic vaccination: improves CD8 T cell responses Together could be enough to stop cart without viral rebound? 1/12/

24 Acknowledgment KUL: Jan Ceuppens, Eric Stevens, Jos Bloemmen, Lieve Mariën, Roger Bouillon, Johan Févery ITM: all HIV(+) particpants of our studies + Virology Lab: Kevin Ariën, Derek Atkinson; Sunita Ballah; Ivan Best; Lotte Bracke; Sandra Coppens, Tessa Dieltjens; Winni De Haes; Youssef Gali; Katrijn Grupping; Leo Heyndrickx, Sabelle Jallow; Jordan Kyongo; Céline Merlin, Jo Michiels; Harr Njai, Pieter Pannus; Charlotte Pollard; Philippe Selhorst; Michael Talledo; Katty Terrazas, Rafaël van den Bergh, Guido van der Groen, Ellen Van Gulck; Yven Van Herrewege, Tine Verdonck, Katleen Vereecken, Johan Vingerhoets, Betty Willems. HIV Immunology: Luc Boel, Luc Kestens, Lieve Penne, Chris Vereecken AIDS Reference Lab: Annelies VD Heuvel, Tine Vermoesen, Katrien Fransen HIV Clinic: Marc Vekemens, Erica Vlieghe, Liesbeth Mertens, Bob Colebunders, Eric Florence EXTERNAL : J Balzarini, D Schols, P Augustyns, A Van Damme (KUL); ); K Thielemans, J Aerts (VUB); N Cools, V Van Tendeloo, Z Berneman, J Joossens, K Augustyns, P Lewi, J Heeres, L Van Laer, G Van Camp (UA); B Verhasselt, M. Praet, W De Spiegelaere, L Vande Kerckhove (U Gent); M Moutschen (U Liège); B Berkhout, A Pasternak (AMC); R Gruters, C Boucher (EMC); T Verrips, N Strokappe, L Rutten (UU); D Corti (Bolzano), R Weiss (London); J Binley (San Diego); E Rich, J Ellner (Cleveland); E Gotuzzo (Lima); M Kizza (Kampala); F Garcia (IDIBAPS); L Martin (CEA Saclay); A Hosmalin (Cochin); B Verrier (Lyon); T Bourlet, O Delézay, B Pozzetto (St Etienne);); F Baleux (Pasteur Paris); H Lortat (Grenoble); R Legrand, N Bosquet, D Desjardin (CEA Paris) 24

AIDS free generation. Bob Colebunders Institute of Tropical Medicine

AIDS free generation. Bob Colebunders Institute of Tropical Medicine AIDS free generation Bob Colebunders Institute of Tropical Medicine Why this optimism? Rapid scale-up of antiretroviral therapy Treatment can prevent new infections Expanded coverage of programmes to prevent