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TRANSCRIPT
Éric A. Cohen, PhDLaboratory of Human
RetrovirologyInstitut de Recherches
Cliniques de Montréal (IRCM)
How close are we to a cure?
HIV Endgame Conference, Toronto
October 25, 2016
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The Canadian HIV Cure Enterprise (CanCURE) Team
Disclosure
• Éric A. Cohen
I have no relationships withcommercial interests to disclose
Outline
1. The Canadian HIV Cure Enterprise (CANCURE)
2. Context and rationale
3. CanCURE objectives and recent progress
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• CanCURE Team project was initiatedfollowing 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 partnershipwith CANFAR and IAS
• IRCM and the Université de Montréal are the host institution
http://www.cancurehiv.org4
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
– P. Ancuta, CR-CHUM– J. Angel, U. of Ottawa– E.A. Cohen, IRCM– J. Estaquier, U. Laval– K. Fowkes, U. Manitoba– A. Mouland, McGill– M. Ostrowski, U. Toronto– J-P Routy, McGill– M.J. Tremblay, U. Laval
• 19 Co-Investigators– B. Bell, U. Sherbrooke– J. Bell, U. Ottawa– R. Bendayan, U. Toronto– Z. Brumme, SFU– M. Brockman, SFU– C. Cheong, IRCM– A. Cochrane, U. Toronto
– N. Chomont, CR-CHUM– A. Gatignol, McGill– É. Haddad, U. Montréal– D. Kaufmann, CR-CHUM– R. Kaul, U. Toronto– A. Kumar, U. Ottawa– M-A Langlois, U. Ottawa– T. Murooka, U. Manitoba– A. Poon, UBC– C. Power, U. Alberta– M. Wainberg, McGill– JC Zúñiga Pflücker, U. Toronto
• Community Liaison– R. Reinhard
CanCURE Participating institutions consist of 10 Canadian Universities and affiliated research centers, including the IRCM, the Team Host Institution
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Context and Rationale
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Current HIV drugs do not eradicate HIV
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Limit of detectionCirculating virus
Time
START STOP
HAART
HIV hides in reservoirs that are not sensitive to current therapies
HIV infection is characterized by high levels of circulating
viruses in the blood
Antiretroviral drugs (HAART) are capable of suppressing HIV, even to undetectable
levels
However, the virus rebounds after
cessation of therapy
Viral reservoirs represent the principal source of viral
persistence during ART and a major obstacle to a cure
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Where does HIV persists?
10Courtesy of Nicolas Chomont
HIV latency, a challenge for host immune defenses
11Deeks et al., Nature Reviews Immunology 2012
HIV latency, a challenge for host immune defenses
12Deeks et al., Nature Reviews Immunology 2012
Failure of effector cell clearancedue to:- Absence of viral protein expression- Viral epitope escape- Host immune exhaustion
Durable reservoirindifferent to treatmentor to any host defensetargeting virus elements
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 Found in virtually every tissue
in the body Originate from self-renewing
tissue-resident macrophages and infiltrating monocyte-derivedmacrophages.
Maintain tissue homeostasis by recognizing and disposing of apoptotic cells in a non pro-inflammatory manner
Provide a critical front line of defense against pathogens, including viruses by eliminatinginfected cells by phagocytosis
HIV-infected Macrophages
Verrolet et al. Blood , 2014
Macrophages as VR candidates • Permissive to productive HIV
infection in vivo and in vitro (express CD4 and CCR5) (Weinberg et al.,1991; Honeycutt et al., 2016)
• Harbor virus for long periodsof time in intracellular virus-containing compartments(VCC) (Groot et al., 2008)
• 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
Honeycutt et al., 2016
Hu-MoM
Macrophages as VR candidates • Presence of proviral DNA
was detected in macrophages isolated fromrectal and ileal tissue (Yukl et al., 2014) as well as myeloidcells isolated from GALT of ART-treated aviremicindividuals (Josefsson et al, 2013)
• However, the fact that macrophage can ingestinfected CD4+ T cells (Baxter et al., 2014) complicates the interpretation
(Yukl et al. 2014)
Sattentau & Stevenson 2016
Cure strategies
17Courtesy Nicolas Chomont
CanCURE objectives and recent progress
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CanCURE Scientific Objectives1) 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/Tetherinsensitizes productively and latently HIV-infected T cells to ADCC mediated by broadly neutralizing antibodies (Pham et al., Scientific Reports)
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HIV-DNA Mainly Persists in Colon and Blood CCR6+ T-Cells during ART
21Gosselin/Wiche-Salinas et al., AIDS, 2016, In Press
Blood Central Memory CCR6+ T-cells Are Enriched in Integrated HIV-DNA During ART
22Gosselin/Wiche-Salinas et al., AIDS, 2016, In Press
Superior HIV Reactivation in CCR6+ Subsets during ART
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The preferential persistence of HIV in colon and blood CCR6+ T-cells during ART needs to be considered for tailored HIV eradication strategies
HIVRNA/Gag dual detectionComplete method
Day -1CD4 T cell isolation
and stimulation
Day 0Surface and ICS antibody
staining mRNA labelling
Day +1Ampli�cation and labelling
Analysis
CD4 isolation
PBMCsSurface staining
ICS for HIV-1 Gag
protein
Label GagPol mRNA
Amplification 2
Ampl
ificat
ion
1 Label amplified
probe
Run on flow cytometer
Rest or stimulateO/N
HIV mRNA
Store 4oC O/N + RNAsin
GagP
ol m
RN
A
Gag Protein
2.8 15.1
0.481.7
Detection of translation-competentreservoirs
Baxter et al. Cell Host and Microbe 2016
This assay is currently adapted to examine HIV persistence in myeloid cells
IFNα Enhances Env Recognition and ADCC by PGT126
Pham et al., 29
…..In a BST2-Dependent Manner
Pham et al., 30
BST2 restriction is normally counteracted by the HIV-1 accessory protein
Enhancement of Virion Tethering by BST2 Sensitizes Reactivated Latent Cells
to ADCC by pGT121
Pham et al., 32
bNAbs: PGT121Restoring BST2 restriction could improve anti-HIV responses and potentially provide a means to eliminate reactivated cellsin latent reservoirs
ThanksIRCM
• Tram NQ Pham• Sabelo Lukhele• Mariana Bego• Frédéric Dallaire• Scott Sugden• Mathieu Dubé
Reagents• J. Robinson, Tulane (17b)• M. Nussenzweig, Rockefeller (3BNC117)• M. Connors, NIH (35O22; 7H6)• D. Burton; P. Poignard , Scripps (PG9; PGT121;
PGT126)• Idera Pharmaceuticals• NIH AIDS Reagent Program
• IRCM Flow Cytometry Core
Healthy volunteers
Clinical Collaborators:P. Larochelle, M. Gauthier and the IRCM Clinic staff
Collaborators• Jean-Pierre Routy, McGill, • Élie Haddad, Université de Montréal, • Winfried Weissenhorn, U. Grenoble-Alpes, • Frank Kirchhoff, University of Ulm, • Wei Cao, MD Anderson Cancer Center, • Yong-Jun Liu, Sanofi• Romas Geleziunas, Gilead• Mario Legault, FRQ-S AIDS Network
CR-CHUM• Amie Baxter• Daniel Kaufmann• Annie Gosselin • Petronela Ancuta• Nicolas Chomont
CanCURE• Robert Reinhardt• Sébastien Sabbagh
THANK YOU
CanCURE MissionThis 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 characterizeand measure viral reservoirs
4. Generate therapeutic approaches that canultimately be tested in human clinical trials.
CanCURE Research Themes• Theme 1: to study the molecular, genetics and functional
characteristics of HIV/SIV persistence in human and animal models (NHP and BLT mice) (Leaders: P. Ancuta & J. Estaquier)
• Theme 2: To define mechanisms governing HIV latency and persistence in macrophages (Leaders: M.J Tremblay & A. Mouland)
• Theme 3: To identify new drug candidates and therapeutic strategies aimed at eliminating HIV persistent infection and to test effective strategies in preclinical studies (Leaders: J. Angel & M. Ostrowski)
• Theme 4: To establish approaches, expertise and infrastructure to conduct HIV Cure clinical trials by examining whether immune-based therapies reduce or eliminate VRs in ART-treated patients (Leaders: J-P Routy & J. Angel)
Scientific Advisory Board
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ERIC J. ARTS
University of Western OntarioLondon, CANADA
MICHAEL M. LEDERMAN
Case Western Reserve UniversityUniversity Hospitals/Case Medical CenterCleveland, USA
OLIVIER SCHWARTZ
Institut PasteurParis, FRANCE
GUIDO SILVESTRI
Emory UniversityYerkes National Primate Research Center, Atlanta, USA
Community Advisory Board• Robert Reinhard – CanCURE Community Liaison• Shari Margolese – At Large and CTN• Renée Masching – Canadian Aboriginal AIDS Network• Tola Mbulaheni – African and Caribbean Council on
HIV/AIDS in Ontario• Jonathan Postnikoff – Positive Living BC• Ron Rosenes – At Large• José Sousa – At Large• Darien Taylor – At large• Wangari Tharao – Women’s Health in Women’s Hands
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