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Latency reversing agents - PowerPoint Presentation

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Latency reversing agents - PPT Presentation

HIV Cure Research Training Curriculum Latency Reversing Agents Module by Scientific Leads David M Margolis CARE and Sharon Lewin DARE Community Leads Cipri Martinez DARE and David Palm CARE ID: 317045

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Slide1

Latency reversing agents

HIV Cure Research Training Curriculum

Latency Reversing Agents

Module by:

Scientific

Leads

: David M. Margolis (CARE) and Sharon Lewin (DARE

)

Community Leads

: Cipri Martinez (DARE) and David Palm (CARE)

The HIV CURE training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field. Slide2

US military cohort (n = 2327, mean age 35) who started ART after 2000, 5-year mortality 0.3

%

Marconi 2010

Predicted survival if HIV+ at 25

yrsSlide3

Combination

HIV

Prevention

Reduce the number of new HIV infections

Treatments

that clear Infection

Reduce the number of

HIV-infected peopleSlide4

Last public appearance of the entire AIDS Quilt, 1996Slide5

Transient “remission” is possible

Two Boston Patients

1,2

The Mississippi Child

3

Treatment

CCR5+/+

bone marrow transplant

Early ART

Remission off ART

3 months and

7 months

2.5 years

Lesson

Delayed viral rebound is achievable

But unknown biomarkers for HIV remission

Henrich

et al.,

J

Infect

Dis

2013,

207(11):1694-702

Henrich

et al.,

Ann Intern Med

. 2014 Jul 22;

Persaud

et al.,

N

Engl

J Med

2013 Nov 7;369(19):1828-35Slide6

Cohen J.

Science

2014 July

Aiming for sustained “remission” off ARTSlide7

Latently

infected T-cells

cART

Homeostatic

proliferationSlide8

Science 2014

The persistent pool of HIV-

1 antiretroviral

therapy can prevent the creation of new latently infected cells, but it does not affect cells in which latency was initially established. Slide9

Residual viral expression

cART

cART

Evidence for residual viral expression in about one third

of

patients on

cART

Buzon

et al.,

Nature Med

2010; 16: 460;

Hatano

et al,

J Infect Dis

2013

Slide10

Anatomical reservoirsSlide11

Archin

et al. 2012

A model using the exposure to

viremia

over time in early infection predicts the frequency of latent infection (“…size of the reservoir…”)Slide12

Ananworanich

et al, 20

th

International AIDS Conference AIDS2014, Melbourne, Australia, 2014

N 20 27 28

100%

74%

14%

Duration of HIV before ART

Very early ART significantly reduces reservoir sizeSlide13

Very early ART reduces reservoirs but…rebound still occurs in SIV

Day of ART initiation post infection

Log HIV DNA in PBMC

Time to viral rebound, days

N=20, SIVmac251 infected macaques treated with

tenofovir

/FTC/

dolutegravir

for 24W

Whitney et al.,

Nature

2014, July 20Slide14

Balance between reservoir and immunity

immunity

latent

virus

Lewin

SR.

Ann

Int

Med

2014 July 22

Boston patients

Mississippi child

VISCONTI patients

(EM>CM)

?Slide15

Activating latent HIV

The Economist, July 17, 2011Slide16

Other Challenges:

Clearance of infected cells

Clearance of

virions

Complete block of new infection

A first step to eliminate latent HIV infection

Anti-latency

therapy

A second step to eliminate latent HIV infection

ImmunotherapySlide17

HIV DNA

HIV US RNA

HIV DNA

HIV proteins

HIV virions

Latent infection

“activate”

Cell death

HDACi

Methylation inh

Cytokines eg., IL7

disulfiram

quinolines

Histone methyl transf inh

BET inh

Activating latent infection: in vitroSlide18

Latently infected cell lines

e.g., J-Lat, ACH2, U1

Constantly dividing

Clonal

Integrate in heterochromatin

Latently infected

primary T-cells

Resting cells

High frequency of latency

Pre and post activation models

Resting CD4+ T-cells

from HIV-infected patients

on ART

Often needs leukapharesis

Frequency of latency low

Mechanistic studies difficult

Highly variable responses

Identifying latency reversing agents (LRA) in vitroSlide19

T-cell activation

PKC

Cytokines

HDACi

other

Spina

et al.,

Plos

Pathogens

2013 Dec;9(12):e1003834

No model ideally represents latently infected ells from patientsSlide20

TF

OFF

HDACi

Histone

deacetylase

inhibitors turn HIV genes “on”Slide21

HIV DNA

HIV US RNA

HIV DNA

HIV proteins

HIV virions

Latent infection

“activate”

Cell death

cART

Latency “activating” agent

cART>3 years

HIV RNA<50 c/ml

CD4>350 cells/ml

Activating latent infection: clinical trialsSlide22

HDACi

Activity

Clinical development

HIV latency

Vorinostat

Pan HDACi

Licensed - CTCL

Single dose

1

Intermittent

2

Continuous

3

Panobinostat

Pan HDACi

Phase III – multiple myeloma

Intermittent dose

4

Romedepsin

Class I HDACi

Licensed - CTCL

Weekly dose

5

EntinostatClass I HDACiPhase III – breast cancerTBD6CTCL – cutaneous T-cell lymphoma1 Archin et al., Nature 2012; 487: 482–85; 2 Archin et al., J Infect Dis 2014; 210: 728–35; 3Elliott J et al., PlosPathogens 2014 (in press); 4Rasmussen et al., Lancet HIV 2014; epub Sept 16; 5Sogaard et al., 20th International AIDS Conference (AIDS2014), Melbourne, 2014; 6Wightman et al., AIDS. 2013 Nov 28;27(18):2853-62 HDACi: activity in cancer and HIVSlide23

Baseline cART

Vorinostat 400 mg

Archin et al.,

Nature

2012; 487: 482

800

600

400

200

60

40

20

0

Pt 1

Pt 2

Pt 3

Pt 4

Pt 5

Pt 6

Relative HIV-1

gag

RNA copies

100

Pt 7

Pt 8

A single dose of

HDACi

vorinostat

activates HIV transcription in vivoSlide24

*

*

cART

Vorinostat 400 mg/day

0

14

84

n=20

Rectal biopsy

*

day

cART

>3 years

HIV RNA<50 c/ml

CD4>500 cells/ml

7

1

3

21

28

Single site, single arm, non-randomised observational study

Elliott et al., Plos Pathogens 2014

Can continuous doses of

vorinostat

“activate” latent infection?Slide25

Fold increase CA-US HIV RNA above baseline

Median fold change max =

7.4 (IQR 3.4, 9.1)

Elliott et al.,

Plos

Pathogens 2014

Vorinostat

induces a significant increase in

unspliced

HIV RNASlide26

But…no change in plasma HIV RNA or HIV DNASlide27

Panobinostat

: a more potent

HDACi

cART

M/W/F

0

28

49

n=16

day

cART

>3 years

HIV RNA<50 c/ml

CD4>350 cells/ml

21

7

14

35

42

M/W/F

M/W/F

M/W/F

Panobinostat

20mg/day, 3 times a week

(Monday, Wednesday, Friday)Slide28

The

HDACi

panobinostat activates latent HIV and produces some virus

days

Fold increase in CA-US RNA

ANOVA p<0.0001

Some increase in virus in plasma in some patients

No change in the reservoir ie no change in HIV DNA

Rasmussen et al., Lancet HIV 2014Slide29

The

HDACi

romidepsin is more potent and activates virus release

Sogaard

et al., 20

th

International AIDS Conference, Melbourne, 2014

No change in HIV DNA following romidepsin x 3

romidepsin

romidepsin

romidepsin

HIV RNA in plasma, copies/ml

Days post first infusionSlide30

What we have found so far:

A

single dose of VOR induces expression of full-length HIV RNA within latently infected resting CD4+ T cells.

The optimal dosing schedule of VOR, and its ability to repeatedly and completely perturb latency in all relevant infected cells, must be establishedSeparately, the potential for VOR to induce antigen expression in (some or all) latently infected cells must be establishedSlide31

Will

HDACi

be enough?

Not all studies show induction of viral expression by HDACi

ex vivoCombinations of anti-latency compounds with different mechanism of action may be more effective

Latently infected cells that express HIV-1 RNA may not all dieSlide32

Latently infected cells are rareSlide33

HIV DNA, RNA, antigen & viruses

HIV Antigen

(protein)

detector

The “Real”

Reservoir

HIV DNA

QVOA

growing virusSlide34

Where can HIV eradication approaches be tested?

HUMANIZED

MICESlide35

When latency is disrupted, mechanisms to kill virus- expressing cells may

be needed

AUGMENT

HIV-1 SPECIFIC IMMUNE RESPONSE WITH HIV-1 VACCINE PRIOR TO

“KICK”

IMPROVE

HIV-1 SPECIFIC CD8 RESPONSE THROUGH

EX VIVO MANIPULATION

EXPANSION orTCR ENHANCEMENTWake up “exhausted” HIV-1 specific cellseg

. Checkpoint inhibitors

Dual function Ab to recruit immune effectors without the need for

HIV-specific cells

INFUSE BROADLY NEUTRALIZING ANTIBODY OR ANTIBODY PRIMED FOR ADCCSlide36

Blocking PD1-PDL1 to boost immune function

Mason et al.,

CROI

2014Slide37

Anti-PDL1 led to successful virus control following ART in half the monkeys

isotype n=5; anti-PDL1 n=9

responders n=4, non-responders n=5

ACTG: single infusion of anti PDL-1 (BMS) to start in 2014Slide38

Current clinical trials to eliminate latently infected cells

Agent

Design

PI (location)

Status

HDACi

Vorinostat

+ vaccine

10 days (acute treated HIV)

Frater (UK)

Approved

Rhomedepsin

Single dose

ACTG (US)

Approved

Rhomedepsin

+ vaccine

Single dose

Ostergaard

(Denmark)

Rhomedepsin

alone (complete)

Other

Disulfiram14 days 500mg/dayDeeks (US)Transient increase in plasma RNA (Spivak CID 2014)Disulfiram3 days500mg-2g/dayDeeks (US)Elliot/Lewin (Australia)Enrolment completeAnti-PDL1 (BMS)Single doseEron (US/ACTG)EnrollingSlide39

Managing the hope and hype

Danish breakthrough for HIV cure expected 'within months'

April

29

th

,

2013Slide40

Expectations of study participants

20 participants with \ HIV infection in

vorinostat

(

HDACi

) trial

Top priority in cure research (%)

McMahon et al., AIDS 2014 (in press)Slide41

Conclusions

We are assembling the tools to design, discover, and test anti-latency therapy

Rational design based on biological understanding of latency

Screen-based discovery

Harnessing the immune response, or other cellular pathways, or new technology to assist in the clearance of persistently infected cells is the next step

Developing platforms and novel assays to allow these developments to be efficiently validated, and safely tested in the

clinicSlide42

AcknowledgementsSlide43

Module Collaborators