Novel approaches for HIV cure

Breach Symposium

Guido Vanham

27 November 2015

Can HIV be eliminated or controlled without ART? C

ircula

ting v

irus

Time

HIV persists during ART

ART

26/10/2015 2

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!

HIV persists as a latent provirus under cART

26/10/2015 3

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

HIV persists as a latent provirus under cART

26/10/2015 4

EC/ES: low plasma viral load without treatment → no or slow disease progression i.e. long-term non-progression (LTNP) Correlates?

Natural HIV control (Elite Controller or Elite Suppressor)

26/10/2015 5

EC/ES: low plasma viral load without treatment → no or slow disease progression i.e. long-term non-progression (LTNP) Correlates?

- Low amount of proviral (integrated) DNA - High activity of CD8 T cells against infected CD4 T cells

HIV-infected CD4 T cells

HIV specific CD8 T cells

HIV progressor Elite controller

Natural HIV control (Elite Controller or Elite Suppressor)

26/10/2015 6

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

New concept of “Functional Cure”

26/10/2015 7

In non-treated HIV infected subjects:

• 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

Kiepiela et al Nat Med 2007

HIV protective CD8 T cell responses?

26/10/2015 8

WBC

Apheresis

Monocytes

Electroporation with HIV-1 gag mRNA

Differentiation

Gag-expressing DC = vaccine

Injection 4X

Dendritic cells (DC)

HIV + subjects under cART

Van Gulck et al. AIDS 2012

DIVA trial: DC therapeutic vaccination

26/10/2015 9

Suppression of vaccine-related HIV is induced in 3/5 patients

V2 T2 V3 T3 V1 V4

w 4

T4 T1

w -3 w 5 w 8 w 12 w 13 w 18 w 0

DIVA trial: induction of CD8 T cells against autologous infected CD4 T cells

26/10/2015 10

Van Gulck et al. AIDS 2012

CD4+ Th

CD40L

CD40

CD4 0 L m RNA

caTLR4 m RNA TLR4

LPS

CD70 CD27

CD8+ CTL

support ac vated T cell survival and prolifera on

induc on of DC matura on

1.

2.

CD7 0 m RNA

3.

Activation signals: TriMix

Gag Pol Vif Nef

Antigen: HIVACAT

In situ loading of DC with antigenic and adjuvant mRNA

! "#$%$&!"!!# $!%&' &() *+' !

IN mRNA

HIV-1 specific CD8 T-cell responses

iHIVARNA principle: Intranodal vaccination with mRNA encoding TriMix and HIVACAT in cART patients

26/10/2015 11

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

Possible strategies for Cure

26/10/2015 12

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

26/10/2015 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) 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

26/10/2015 14

The Berlin patient

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

Genetic therapy deleting CCR5

26/10/2015 15

Future therapy: Deletion CCR5 in haematopoietic stem cells (HSC) ?

By CCR5 deletion

26/10/2015 16

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

Possible strategies for Cure

26/10/2015 17

Principle: Some drugs (e.g. HDAC inhibitors) can activate the latent provirus → virus production may kill infected cells

Anti-Latency treatment

26/10/2015 18

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?

Anti-Latency treatment

26/10/2015 19

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

Anti-Latency treatment

26/10/2015 20

Courtesy of O. Søgaard, Aarhus University

Clinical trail of HDACi Romidepsin (under cART protection)

26/10/2015 21

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?

Anti-Latency treatment

26/10/2015 22

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?

23 1/12/2015

Integration of various “Cure” approaches

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) …

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