1-no ars final au edited hiv 17 chi dr deeks · pdf fileicbs anti-inflammatory rx sanctuary...

5/11/2017

1

Steven G. Deeks, MDProfessor of Medicine

University of California San FranciscoSan Francisco, California

HIV Cure Research Questions and a Few Answers

FORMATTED: 04/13/17

Chicago, Illinois: May 10, 2017

Slide 2 of 42

Financial Relationships With Commercial Entities

Dr Deeks has served as a consultant for EMD Serono, Inc, on the scientific advisory board for BryoLogyx, Inc, and has received research support from Merck, ViiV Healthcare, and Gilead Sciences, Inc. (Updated 04/13/17)

Slide 3 of 42

Learning Objectives

After attending this presentation, learners will be able to: Describe where HIV “resides” during long-term

antiretroviral therapy Outline the major causes of HIV persistence during

therapyDescribe the barriers to measuring the HIV reservoirDescribe viable pathways towards a cure for HIV

infection


5/11/2017

2

Slide 4 of 42

HIV Cure: Lots of questions and a few answers

• How much is there?

• How stable is the reservoir?

• Where does it reside?

• Can it be measured?

• Can latency be prevented?

• Can latency be reversed?

• Can the virus be controlled?

• How much should it cost?

Slide 5 of 42

What do we know about the size and stability of the “reservoir”?

Slide 6 of 42

0 5 10 15 20 25 30 350

1

2

3

4

5

6

7

8 36160

3625336348

3634936488

3654436661

Start Treatment

3635336166

Weeks Post Infection

Log

vRN

A C

opie

s/m

l

Although ART reduces viremia > 6 to 7 log10 some virus persists indefinitely (0.1-3 copies RNA/mL)Source of the viremia is not known but it is not from an actively replicating population


5/11/2017

3

10104

103

105 (spleen)106 (large bowel)

105 (small bowel)106-7 (LN)

10 (kidney)

The vast majority of HIV resides in the lymphoid organs, most of it assumed to be in CD4+ T cells, but the macrophage-rich tissues are understudied

?

Courtesy of Tim Schacker

(HIV+ cells/gram tissue)

The “active” reservoir in nodes declines slowly over time and appears to be correlated with the level of lymphoid inflammation (germinal centers)

Slide 9 of 42

Slide 9 of 42

What do we know about the types of CD4+ T cells that harbor HIV during ART?


5/11/2017

4

Slide 10 of 42

Modest enrichment of HIV has been reported in certain CD4+ T cell subsets

• Activated/proliferating –HLA-DR, PD-1, LAG-3, CTLA-4, TIGIT

• T follicular helper cells (nodes)• Migrating: CCR6, ⍺4 β7• Effector cells

1Chomont, Nat Med 09. 2Murray JV 14. 3Hatano JID 12. 4Cockerham PLoS ONE 14. 5Wang JID 14. 6Chun JCI 05. 7Riddler (unpublished). 8Lewin (unpublished). 9Hatano JID 14. 10Frometin (unpublished)

HIV enriched (100 to 1000 fold) in CD32a-expressing CD4 + T cells

Most (> 50%) of reservoir may be in these cells, even though they are rare (~1% of CD4+ T cell population)

Slide 12 of 42

Slide 12 of 42

How does HIV persist indefinitely?


5/11/2017

5

Slide 13 of 42

Does HIV replicate (or spread) during ART?

Early evolution Low ART, CTL

in LN Intensification

No evolution Pre-ART virus

rebounds No failure

Slide 14 of 42

Up to 50% of infected cell population (blood) is clonal in nature

Integration sites enriched for genes associated with cell growth/cancer

Cell proliferation maintains the reservoir during ART

Slide 15 of 42

B cell follicles: a relative immune-privileged sanctuary for HIV-infected Tfh T cells

Fukazawa et al., Nature Med 2015; Banga et al., Nature Med 2016; Leong et al., Nature Immunol 2016


5/11/2017

6

Slide 16 of 42

Can the reservoir be measured?

Slide 17 of 42

HIV ReservoirVast majority of genomes are defective

• Population of replication-competent HIV that persists during ART and ignites new rounds of replication when ART is stopped

• Rare, tissue-based, may be impossible to directly measure

Slide 18 of 42

Virus in blood: often clonal and archival

Virus in LN: enriched in the follicles (Tfhcells) and actively replicating

Blood and tissue reservoirs are not the same


5/11/2017

7

Slide 19 of 42

• Cancer: rare tissue based cells that are similar to healthy cells and hard to detect

• Sensitive tracers that detect cancer (or HIV) being developed

Slide 20 of 42

When is the reservoir established?

Slide 21 of 42

At about the time HIV RNA becomes detectable, the reservoir size begins to increase dramatically, with an apparent 100-fold increase over the next two weeks

Reservoir largely established by week 4 of infection


5/11/2017

8

Slide 22 of 42

Very early ART reduces the reservoir but is not curative

N=8; ART in Fiebig I for >96 weeks; VL<50 c/ml; CD4>400 cells/ul

Ananworanich J et al., CROI 2017, Seattle, WA

ART (PrEP) during “Fiebig 0” Stage

Slide 24 of 42

• 20 adults (and one child) who started therapy early (but not in “hyperacute” stage), remained on therapy for years, and had no rebound after stopping therapy

• Low reservoir size, low T cell activation and strong immune responses


5/11/2017

9

Slide 25 of 42

What will a cure have to look like to have a global impact?

Slide 26 of 42

• Efficacy: aviremia in absence of therapy > 2 years; early failure is tolerable, late failures must be rare

• Product: oral/parental; administered for limited period of time (e.g., 6 months); specialized (tertiary) care not required

• Target Population: effective ART initiated at any stage and in all populations (gender, subtype)

• Long-term safety: comparable to ART, transmission risk negligible

• Cost: < $1400 (RLS)

Slide 27 of 42

How will we cure HIV infection?


5/11/2017

10

Slide 28 of 42

Viable pathways towards a durable remission/cure

• Gene and cell-based therapy

– Proof of concept: Berlin Patient

– Multiple feasible pathways, none yet scalable

• Early ART

– Sterilizing cure not possible (Mississippi case, Fiebig 0 case)

– Post-treatment control (VISCONTI) occurs rarely when ART is started early (not acute)

• Immunotherapy: remission (post-treatment control)

• Shock and kill: reservoir reduction

Slide 29 of 42

How will we cure HIV infection?

In absence of heroic interventions (e.g., gene therapy), it is likely that a remission will likely be easier to achieve than a complete cure

Several viable combinatorial approaches are now moving towards proof-of-concept testing

Slide 30 of 42

All models of durable SIV/HIV remission suggest that durable control of established infection will require (1) low disease burden, (2) low inflammation and (3) sustained T cell responses that are primed, reside in tissues, and target susceptible epitopes

These same attributes apply to cancer immunotherapy


5/11/2017

11

Slide 31 of 42

HIV Remission

Vaccine

CMV

DNA/RNA

Adeno/MVA

Adjuvants

TLR agonists

Immune-modifying

ICBs

Anti-inflammatory Rx

Sanctuary Disruption

CD20 antibody

Cytokines

Low Reservoir

Early ART

LRAs

Slide 32 of 42

Therapeutic vaccines: Safe, generally immunogenic and associated with no benefit in most studies and modest benefit in some studies

Trial Regimen Comment Author/Paper

ACTG 5068 ALVAC (vCP1452) Intermitting interruptions but not vaccine associated with reduced VL

Jacobson, JID 2006

ACTG 5024 ALVAC (vCP1452) + IL-1

0.5 log VL reduction during ATI Kilby, JID 2006

ACTG 5097 Ad5 0.24 log10 Schooley, JID 2010

MANON-02 ALVAC-HIV No VL effect; activated CD4 cells may have induced early failure

Papagno, AIDS 2011

Bionor p24 peptide mixture (Vacc-4x)

ATI: no VL effect at primary endpoint, mild benefit at later time points

Pollard, Lancet HIV 2014

ERAMUNE 02

DNA prime/MVA boost No effect (HIV DNA) Achenbach, Lancet HIV 2015

GeneCure Replication-defective HIV with VZV fusion protein (HIVAX)

Reduced VL set-point (compared to historical data)

Tung, Vaccine 2016

GeoVax DNA prime/MVA boost (virus-like particles)

No apparent effect during ATI (uncontrolled) Thompson, PLoS ONE 16

ACTG 5281 Gag/Pol, Nef/Tat/Vif/Env and IL-12 plasmids (Profectus)

Minimal CD4 effects, no CD8 effects, low dose IL-12 better than high dose IL-12

Jacobson, JAIDS 2016

BCN 02 ChAdV63.HIVconsv + MVA.HIVconsv

5/13 controlled (ATI) Mothe, CROI 17

Slide 33 of 42

Immunotherapy for HIV infectionTwo decades of largely failed approaches

• Weak immunogenicity

– Pre-existing immuno-dominant responses

– CTL escape

• Inflammation and counter-regulatory immunosuppression

• High virus burden

• Immune-privileged tissue sanctuaries


5/11/2017

12

Slide 34 of 42

Vaccine (Ad26/MVA prime-boost) alone had minimal effect on reservoir

Vaccine + TLR7 agonist (Gilead) reduces reservoir during ART and controls SIV post-ART

Slide 35 of 42

BCN02 Trial: HIV vaccine with latency reversal induces sustained HIV control in 5 individuals (8 individuals failed)

Slide 36 of 42

Cancer immunotherapy is reshaping a fatal and progressive disease much as ART reshaped HIVMost therapies aim to enhance capacity of CD8+ T cells to recognize and clear rare tissue-based cells that reside in inflamed tissues

• Upregulation of checkpoint blockers (PD-1, CTLA-4)

• Immunosuppressive cytokines (TGF-β, IL-10, IDO)

• Immunosuppressive immune cells (T-regs, MDSCs)


5/11/2017

13

Slide 37 of 42

How will we reduce the reservoir size to a level such that the immune system can conceivably control what is left?

Slide 38 of 42

Shock and KillGoals have shifted from complete eradication (“cure”), which is likely not possible, to reduction, which will be essential for immune control (“remission”)

Slide 39 of 42


5/11/2017

14

Slide 40 of 42

State of the ART: 2017

• Location, size and stability of reservoir remains to be characterized– Measuring total body replication-competent reservoir not possible

– Cellular reservoirs now being explored

• Mechanisms for persistence known: latency, poor CTL, cell proliferation

• The reservoir can be reduced with early ART and cell therapy but not with anything scalable

• It is possible to reverse latency (shock) but the impact on the reservoir is negligible and most approaches are toxic

• Therapeutic vaccines work in monkeys and perhaps humans

• Combination approaches will be needed and are now moving into the clinic (era of “experimental medicine”)

Slide 41 of 42

Acknowledgements

Steven G. Deeks, MDProfessor of Medicine

University of California San FranciscoSan Francisco, California

HIV Cure Research Questions and a Few Answers

FORMATTED: 04/13/17



1-no ars final au edited hiv 17 chi dr deeks · pdf fileicbs anti-inflammatory rx sanctuary...

Documents