The Canadian HIV Cure Enterprise (CanCURE) Team Éric A. Cohen, PhD Laboratory of Human Retrovirology Institut de Recherches Cliniques de Montréal (IRCM) How close are we to a cure? HIV Endgame Conference, Toronto October 25, 2016 1
Disclosure • Éric A. Cohen I have no relationships with commercial interests to disclose
Outline 1. The Canadian HIV Cure Enterprise (CANCURE) 2. Context and rationale 3. CanCURE objectives and recent progress 3
• CanCURE Team project was initiated following a RFA on HIV Cure launched by the CIHR HIV/AIDS initiative in January 2013 • CanCURE is funded for 5-years (Jan 1, 2014- Dec 31st, 2018) by the CIHR in partnership with CANFAR and IAS • IRCM and the Université de Montréal are the host institution 4 http://www.cancurehiv.org
CanCURE Mission To understand HIV persistence during antiretroviral therapy (ART) and to harness this knowledge towards the development of HIV cure interventions
CanCURE Team • 9 Principal Investigators – N. Chomont, CR-CHUM – P. Ancuta, CR-CHUM – A. Gatignol, McGill – J. Angel, U. of Ottawa – É. Haddad, U. Montréal – E.A. Cohen, IRCM – D. Kaufmann, CR-CHUM – J. Estaquier, U. Laval – R. Kaul, U. Toronto – K. Fowkes, U. Manitoba – A. Kumar, U. Ottawa – A. Mouland, McGill – M-A Langlois, U. Ottawa – M. Ostrowski, U. Toronto – T. Murooka, U. Manitoba – J-P Routy, McGill – A. Poon, UBC – M.J. Tremblay, U. Laval – C. Power, U. Alberta – M. Wainberg, McGill • 19 Co-Investigators – JC Zúñiga Pflücker, U. Toronto – B. Bell, U. Sherbrooke – J. Bell, U. Ottawa – R. Bendayan, U. Toronto • Community Liaison – Z. Brumme, SFU – R. Reinhard – M. Brockman, SFU – C. Cheong, IRCM – A. Cochrane, U. Toronto CanCURE Participating institutions consist of 10 Canadian Universities and 6 affiliated research centers, including the IRCM, the Team Host Institution
Context and Rationale 7
Current HIV drugs do not eradicate HIV However, the virus HIV infection is characterized Antiretroviral drugs (HAART) are capable of rebounds after by high levels of circulating suppressing HIV, even to undetectable cessation of therapy viruses in the blood levels START STOP HAART Circulating virus Limit of detection Time HIV hides in reservoirs that are not sensitive to current therapies 8
Viral reservoirs represent the principal source of viral persistence during ART and a major obstacle to a cure 9
Where does HIV persists? 10 Courtesy of Nicolas Chomont
HIV latency, a challenge for host immune defenses 11 Deeks et al. , Nature Reviews Immunology 2012
HIV latency, a challenge for host immune defenses Durable reservoir indifferent to treatment or to any host defense targeting virus elements Failure of effector cell clearance due to: - Absence of viral protein expression - Viral epitope escape - Host immune exhaustion 12 Deeks et al. , Nature Reviews Immunology 2012
While extensive efforts have been deployed in the direction of eliminating HIV-1 memory CD4+ T-cell, the predominant VR, much less is known about the contribution of myeloid cells and particularly macrophages to the overall HIV reservoir It will be difficult to achieve a cure for HIV-1 without considering all potential VRs
Macrophages HIV-infected Macrophages Found in virtually every tissue in the body Originate from self-renewing tissue-resident macrophages and infiltrating monocyte-derived macrophages. Maintain tissue homeostasis by Verrolet et al. Blood , 2014 recognizing and disposing of apoptotic cells in a non pro- inflammatory manner Provide a critical front line of defense against pathogens, including viruses by eliminating infected cells by phagocytosis
Macrophages as VR candidates Hu-MoM • Permissive to productive HIV infection in vivo and in vit r o (express CD4 and CCR5) (Weinberg et al.,1991; Honeycutt et al., 2016) • Harbor virus for long periods of time in intracellular virus- containing compartments (VCC) (Groot et al., 2008) Honeycutt et al., 2016 • They are resistant to HIV-1- induced apoptosis (Carter et al., 2008) • They can harbor virus in a latent state or in a state of very low expression in vitro (Kumar et al. Viruses, 2014) Sattentau & Stevenson , 2016
Macrophages as VR candidates • Presence of proviral DNA was detected in macrophages isolated from rectal and ileal tissue (Yukl et al., 2014) as well as myeloid cells isolated from GALT of ART-treated aviremic (Yukl et al. 2014) individuals (Josefsson et al, 2013) • However, the fact that macrophage can ingest infected CD4+ T cells (Baxter et al., 2014) complicates the interpretation Sattentau & Stevenson 2016
Cure strategies 17 Courtesy Nicolas Chomont
CanCURE objectives and recent progress 18
CanCURE Scientific Objectives 1) Identify, characterize and exploit insufficiently characterized properties of myeloid cells, especially macrophages, and additional lymphoid cell subsets within mucosal compartments that act as VRs; 2) Conduct detailed mechanistic studies aimed at understanding how these VRs are established and maintained; 3) Identify new drug candidates that reverse virus latency/persistence in multiple cross-acting VRs, and evaluate novel therapeutic strategies that enhance immune control and/or induce effective clearance of VRs; 4) Test whether immune-based therapies control or reduce VR in ART-treated HIV-infected patients in clinical trials
CanCURE Recent Progress • HIV persists in CCR6+ CD4+ T cells from Colon and Blood during antiviral Therapy (Gosselin/Wiche Salinas et al., AIDS , 2016, In Press) • Single-cell characterization of viral translation- competent reservoirs in HIV-Infected individuals (Baxter et al, Cell Host & Microbe , 2016) • Enhancing virion tethering by BST2/Tetherin sensitizes productively and latently HIV-infected T cells to ADCC mediated by broadly neutralizing antibodies (Pham et al., Scientific Reports ) 20
HIV-DNA Mainly Persists in Colon and Blood CCR6+ T-Cells during ART 21 Gosselin/Wiche-Salinas et al., AIDS, 2016, In Press
Blood Central Memory CCR6+ T-cells Are Enriched in Integrated HIV-DNA During ART 22 Gosselin/Wiche-Salinas et al., AIDS, 2016, In Press
Superior HIV Reactivation in CCR6+ Subsets during ART The preferential persistence of HIV in colon and blood CCR6+ T-cells during ART needs to be considered for tailored HIV eradication strategies 23
HIV RNA/Gag dual detection Complete method Day -1 Day 0 Day +1 CD4 T cell isolation Surface and ICS antibody Ampli� cation and labelling and stimulation staining mRNA labelling Analysis Surface staining PBMCs m p l i f i c a t i o n A 2 Label amplified ICS for HIV-1 Gag probe protein Amplification 1 CD4 isolation Run on flow L a b e HIV mRNA l G cytometer a g P m o R l N A 15.1 2.8 GagPol mRNA Store 4 o C O/N + 0.4 Rest or stimulate 81.7 RNAsin O/N Gag Protein
Detection of translation-competent reservoirs This assay is currently adapted to examine HIV persistence in myeloid cells Baxter et al. Cell Host and Microbe 2016
IFNα Enhances Env Recognition and ADCC by PGT126 Pham et al., 29
…..In a BST2-Dependent Manner BST2 restriction is normally counteracted by the HIV-1 accessory protein Pham et al., 30
Enhancement of Virion Tethering by BST2 Sensitizes Reactivated Latent Cells to ADCC by pGT121 bNAbs: PGT121 Restoring BST2 restriction could improve anti-HIV responses and potentially provide a means to eliminate reactivated cells Pham et al., in latent reservoirs 32
Thanks IRCM Collaborators • Tram NQ Pham • Jean-Pierre Routy, McGill, • Sabelo Lukhele • Élie Haddad, Université de Montréal, • Mariana Bego • Winfried Weissenhorn, U. Grenoble-Alpes, • Frédéric Dallaire • Frank Kirchhoff, University of Ulm, • Scott Sugden • Wei Cao, MD Anderson Cancer Center, • Mathieu Dubé • Yong-Jun Liu, Sanofi CR-CHUM • Romas Geleziunas, Gilead • Amie Baxter • Mario Legault, FRQ-S AIDS Network • Daniel Kaufmann Reagents • Annie Gosselin • J. Robinson, Tulane (17b) • Petronela Ancuta • M. Nussenzweig, Rockefeller (3BNC117) • Nicolas Chomont • M. Connors, NIH (35O22; 7H6) CanCURE • D. Burton; P. Poignard , Scripps (PG9; PGT121; • Robert Reinhardt PGT126) • Sébastien Sabbagh • Idera Pharmaceuticals Clinical Collaborators: • NIH AIDS Reagent Program P. Larochelle, M. Gauthier • IRCM Flow Cytometry Core and the IRCM Clinic staff Healthy volunteers
THANK YOU
CanCURE Mission This collaborative effort engages basic and clinical scientists as well as members of the community in a research effort to: 1. Characterize mechanisms of HIV persistence in the presence of ART 2. Develop cell-based and animal model systems in which persistent infection can be investigated and therapeutic interventions can be tested. 3. Develop new assays to accurately characterize and measure viral reservoirs 4. Generate therapeutic approaches that can ultimately be tested in human clinical trials.
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