Post CROI 2019 Ontwikkelingen op het gebied van HIV cure Annemarie Wensing, MD, PhD Laura Huyveneers, MD DISCLOSURE BELANGEN - AMJ Wensing

* Vergoedingen gaan naar het UMC Utrecht HIV cure

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Latent reservoir in ART blood and tissues

HIV replication

Inspired by Nicholos Chomont. HIV reservoirs and strategies towards an HIV cure. HIV-NAT 2017 Cure Strategies

Measuring the reservoir 1. Quantification 2. Characterization 3. Mapping

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early Flush out Deplete Render Vaccine Immuno- the latent infected uninfected therapy ART cells reservoir cells resistant to HIV Measuring the reservoir: Quantification

1. Quantification 2. Characterization 3. Mapping

Barton et al. Curr HIV/AIDS rep 2016 Measuring the reservoir: Characterazation

Next generation sequencing

T T C A G A T T C C G A • Intact or defect provirus Ching-Lan Lu. Relationship between intact HIV-1 proviruses and plasma rebound virus. Abstract 340.

Andrew Rambaut, University of Edinburgh • Compartimentalization Richard Price. Rebound of HIV-1 in cerebrospinal fluid after 1. Quantification treatment interruption. Abstract 391. 2. Characterization • Production or replication 3. Mapping

Elias K Halvas. Nonsuppressible viremia on ART from large cell clones carrying intact proviruses. Abstract 23. Measuring the reservoir: Mapping

Barone et al. Frontiers in Immunology. 2016 Goltsev et al. Cell. 2018

• Highly sensitive new quantification techniques, active cells vs non active producing cells (RNA scope and DNA scope)

• Viral reservoirs in context of their immune neighborhoods and inflammatory landscapes in different compartiments

Jacob Estes. Novel imaging approaches to characterize and quantify viral reservoirs. Abstract 4. Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early ART Flush out Deplete Render Vaccine Immuno- uninfected therapy the latent infected cells reservoir cells resistant to HIV

Inspired by Nicholos Chomont. HIV reservoirs and strategies towards an HIV cure. HIV-NAT 2017 Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early ART Flush out Deplete Render Vaccine Immuno- uninfected therapy the latent infected cells reservoir cells resistant to HIV

Maud Mavigner Targeting the noncononical NF-KB pathway reverses SIV latency. Abstract 22 Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early ART Flush out Deplete Render Vaccine Immuno- uninfected the latent infected cells therapy reservoir cells resistant to HIV

Inspired by Nicholos Chomont. HIV reservoirs and strategies towards an HIV cure. HIV-NAT 2017 Reduce the reservoir: Render uninfected cells resistant to infection CCR5

Tricia H. Burdo Pablo Tebas Ex vivo and in vivo editing of the SIV genome in Delayed viral rebound during ATI after nonhuman primates by CRIPR-CAS9. infusion of CCR5 ZFN-treated CD4 T cells. Abstract 24 Abstract 25 CCR5 gene editing

Tebas. CROI 2019. Abstr 25

RNA-based transfection

Cyclophosphamide for engrafment

Wildtype CCR5 and Heterozygous CCR5∆32

Tebas et al. NEJM 2014 Time to virological rebound Viral load during ATI

• No related serious adverse events • Modest delay compared to historical • Greater levels of disruption after CTX ACTG control and in CCR5∆32 heterozygous

Tebas. CROI 2019. Abstr 25 Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Render Early ART Flush out Deplete uninfected VaccineVaccine Immuno- the latent infected cells therapy reservoir cells resistant to HIV

Inspired by Nicholos Chomont. HIV reservoirs and strategies towards an HIV cure. HIV-NAT 2017 Cure Strategies

IciStem cohort 48 patients registered with a hematological condition 39 received Stem cell transplantation Sampled according to IciStem protocol Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early Flush out Render Vaccine Immuno- Deplete uninfected ART the latent infected cells therapy reservoir cells resistant to HIV Reduce the reservoir: Deplete infected cells

Treated for AML • Myeloablative allogenic HSCT (2x) • Full body radiation • Graft vs. Host disease • CCR5∆32 homozygous donor HIV GP120

CD4 Coreceptor T-cell CCR5 CXCR4 ART stopped without viral rebound >10 years • No residual virus detected in extensive search Timothy Ray Brown by HIV equal The “Boston patients” • Viral rebound in 12/32 weeks after wildtype HSCT Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir Ravindra K Gupta.reservoir reservoir “London patient” Sustained HIV-1 remission following homozygous CCR5 delta32 allogenic HSCT. Abstract 29

Render Early Flush out Björn-VaccineErik O Jensen. Immuno- Deplete uninfected “Duesseldorf patient“ ART the latent cells therapy infected Analytic treatment interruption (ATI) reservoir resistant to cells after allogenic CCR5-D32 HSCT for HIV AML in 2013. Abstract 394 IciStem #36 The “London patient” Second Case of Viral Suppression Without ART After CCR5Δ32 Homozygous Allo-HSCT

Gupta. CROI 2019. Abstr 29. Reproduced with permission by CCO. IciStem #36: The “London patient”

Viral reservoir quantification

Gupta. CROI 2019. Abstr 29. IciStem #36: The “London patient” Viral reservoir characterization HIV-1 coreceptor tropism pre-SCT Immune responses post-SCT

CCR5 genotyping Pre-SCT: wildtype Post-SCT: CCR5∆32

Gupta. CROI 2019. Abstr 29/ Nature 2019. Time (days) IciStem # 19: The “Düsseldorf patient”

ATI 3 months without viral rebound IciStem # 19: The “Düsseldorf patient”

• No proviral DNA detectable in blood, bone marrow, lymph nodes, liqour and rectum • DNA and RNA scope • Western blot fading Overview CCR5∆32 homozygous HSCT transplants

“” “London patient” “Düsseldorf patient” CCR5∆ 32 heterozygous WT CCR5 homozygous WT CCR5 homozygous

R5 tropic HIV infection R5 tropic HIV infection R5 tropic HIV infection Acute myeloid leukemia Hodgekin lymphoma Acute myeloid leukemia 2 HSCTs Single HSCT Single HSCT Total body irradiation No irradiation No irradiation Full intensity conditioning Reduced intensity Full intensity conditioning conditioning Mild GvHD (skin) Mild GvHD (skin) Moderate GvHD (liver) 100% T-cell donor 100% T-cell donor 100% T-cell donor chimerism chimerism chimerism Cure Strategies Measuring the reservoir Antibodies directed to: • HIV • Immune cells

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early ART Render Deplete Flush out Vaccine Immuno- uninfected cells infected the latent therapy resistant to cells reservoir HIV

Michel Nussenzweig. Bernard Fields lecture: discovery and development of HIV broadly neutralizing antibodies. Abstract 10

Inspired by Nicholos Chomont. HIV reservoirs and strategies towards an HIV cure. HIV-NAT 2017 Broadly neutralizing antibodies (BnAbs)

Mendoza et al. Nature. 2018 Cure Strategies

Measuring the reservoir

To limit the To reduce the size of To control the establishment of the the reservoir reservoir reservoir

Early ART Flush out Deplete Render Vaccine Immuno- uninfected therapy the latent infected cells reservoir cells resistant to HIV

Inspired by Nicholos Chomont. HIV reservoirs and strategies towards an HIV cure. HIV-NAT 2017 Summary and conclusion

Long term HIV-1 remission is not a miracle

Promising steps in characterisation of the reservoir are made

Several mechanistic studies on non ideal cohorts

Collaborative research with in depth sampling will be a next step to make progress towards a generalized cure Acknowledgements

The IciStem consortium Jürgen Kuball (Hematologist, University Medical Center Utrecht) Javier Martinez-Picado (Co-PI, Monique Nijhuis (Virologist, Virologist, AIDS Research Institute IrsiCaixa, University Medical Center Utrecht) Barcelona) Vanderson Rocha (Hematologist Annemarie Wensing (Co-PI, Clinical Cord Blood Bank Specialist Oxford University) Virologist, University Medical Center Utrecht) Asier Sáez-Cirión (Immunologist,Pasteur Institute, Paris) Jose L. Díez Martin (Hematologist, Hospital Gregorio Marañón, Madrid) Julian Schulze zur Wiesch (Infectious disease specialist, UMC Hamburg- Mi Kwon (Hematologist, Hospital Gregorio Eppendorf) Marañón, Madrid) Gero Hütter (Hematologist, Cellex Dresden)

IciStem researchers & project management Germany: Dieter Häussinger, Guido Kobbe, Björn Jensen (University Hospital Düsseldorf), Rolf Kaiser, Elena Knops (University of Cologne) María Salgado, Judith Dalmau (AIDS Research Institute IrsiCaixa, Barcelona), Arjen Stam, Kobus Bosman, Antoinet van Kessel (University Medical Center Utrecht), Italy: Alessandra Bandera, Antonio Muscatello and Dr. Alessandro Soria (San Pascual Balsalobre Lopez (Hospital Gregorio Marañón, Madrid), Gerardo Hospital, Monza, Italy). Johanna Eberhard (UMC Hamburg-Eppendorf) Netherlands: Pauline Ellerbroek, Lodewijk Brosens, Anke Bruns, Erik van Scientific Advisors: Maarseveen (UMC Utrecht) Jan van der Meer, Sacha Zeerleder (AMC) Koen van Besien, Jan van Lunzen Spain: Ildefonso Espigado (University Hospital Virgen del Rocío, Seville)

IciStem participants United Kingdom: Kavita Raj, Fabio Cruciani, Varun Mehra, Carmel Rice, (Kings College Hospital, London) Belgium: Linos Vandekerckhove, Marie-Angélique de Scheerder, Eva Steel Angela Bailey (Imperial College Healthcare NHS Trust, London) (University of Ghent) Waseem Qasim (Institute of Child Health & Great Ormond Street Hospital, London) Canada: Lisa Barrett, Sharon Oldford, Nate Stepner, Marina Turner (NSHA/Dalhousie University, Halifax) Acknowledgement

Translational Virology, UMCU