HIV cure on trial: hype or hope?

Anton Pozniak

Consultant Physician

Director of HIV Services

Chelsea and Westminster Hospital

London, UK

Why Cure HIV?

HAART does not cure HIV

Short-lived infected cell

Long-lived infected cell(latently infected)

HIV persistence during therapyARV naive patient

Short-lived infected cell

Long-lived infected cell(latently infected)

HIV persistence during therapy-- Patient on HAART

Antiretroviral therapy

Short-lived infected cell

Long-lived infected cell(latently infected)

HIV persistencepatient who has stopped HAART

Untreated HIV infection

Short-lived infected cell

Long-lived infected cell(latently infected)

Virus particle

Non-infected cell

Treated with optimal antiretroviral therapy

Prevents disease progression but no cure (rare infected cells persist)

•Latently infected CD4+ T lymphocytes are rare in vivo:

•Approximately 1 per 106 total resting CD4+ T cells

•Probably constitute around 105-106 cells per patient

Rose Bowl Capacity = 92,542

Approximately 1 per million resting CD4+ T cells harbor a latent provirus.

To cure the infection we need to do this with 1,000,000(one million) cells hidden in this way.

Like finding one person in 11 football stadiums.

Finding and destroying the latent virus pool

So What Lessons Have We Learned about Cure so far?

http://pozmagazine.tumblr.com/post/5137593713/timothy-brown-a-k-a-the-berlin-patient-is-the

The “Berlin Patient”

Treated with optimal antiretroviral therapy

Ablative therapy (destroys immune system)

X

Followed by transplant with HIV-resistant cells

Short-lived infected cell

Long-lived infected cell(latently infected)

Virus particle

Non-infected cell

HIV-resistant cells

Might allow cure of infection (elimination of all replication-competent virus)

scBMT(X2)

Donor

Hütter. NEJM. 2009; Allers. Blood. 2010

HIV-1+AML

CCR5+

CCR5–

HIV-1– ?

CCR5–

off ARTno viral rebound

Long-term control of HIV by CCR5 Δ32/Δ32 stem cell transplantation

Chemotherapy (x4)Total-body irradiation (x2)

The Berlin Patient – What did we learn

• Replication competent reservoirs can be eliminated

• Long term viral control can be maintained despite waning immunity

http://www.cnn.com/2013/12/07/health/hiv-patients/

BUT…………….Bone marrow transplant with unprotected (not HIV-resistant) donor cells “the 2 Boston Patients” delayed viral rebound

But did not prevent it...

More lessons…..The “Mississippi baby”

Detection of Human Immunodeficiency Virus Type 1 (HIV-1) Infection in the Child.

Persaud D et al. N Engl J Med 2013;369:1828-1835.

http://www.nejm.org/doi/full/10.1056/NEJMoa1302976#t=article

Solid arrow = Last prescription for ART filledDashed arrow = Time of last ART administration

Results so FarOnly One patient cured!!

What else?Early treatment

Untreated HIV infection in newborn- Limited reservoir cells?

Short-lived infected cell

Long-lived infected cell(latently infected)

Virus particle

Non-infected cell

Early treatment with potent antiretroviral therapy

Still under investigation- Perhaps the early treatment prevented establishment of latent reservoir

The “VISCONTI cohort”

Viro-Immunologic Sustained COntrol after Treatment Interruption

“Functional cure” for some patients?

Long-term control of viremia and stable CD4+ T cell counts in fourteen patients after interruption of antiretroviral treatment initiated in primary HIV-1 infection.

Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211

Grey Shading = Periods where patients received therapy

14 post-treatment controllersStarted HAART within 2 months of primary infection At around 3 years interrupted treatmentControl viremia out to 90 months

No immune correlates of protectionLow reservoir A select group?

Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211

Visconti patients

Other Strategies to Cure HIV

Treatmentoptimization& intensification

(eliminateall replication)

Reversal of HIV latency

(increase viral production)

Immune-basedtherapies

(reverse pro-latency signaling)

Therapeuticvaccination

(to enhance host-control)

Genetherapy

Experimental activation-elimination approaches to deplete latent HIV

“Kick and Kill”

25D. D. Richman et al., Science 323, 1304 -1307 (2009)

Purging the Reservoir

Turning on latently infected cells

Kick and Kill Strategy

Kick strategies

HDACi turn HIV genes “on”

TF

OFF

Bolden, Nat Rev Drug Disc 2006; Prince. Clin Canc Res 2009; Contreras, J Biol Chem 2009;Archin AIDS Res Hum Retrovir 2009; Reuse, PLoS One 2009; Burnett , J Virol 2010

HDACi

DNAnucleosomes

HDAC inhibitors in trials

Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt. 80

20

40

60

200

400

600

800

100

Baseline ART

VOR 400 mg

Re

lativ

e H

IV-1

ga

g R

NA

co

pie

s

Shocked but not KilledHDACi Panobinostat

days

Fold

incre

ase in C

A-U

S R

NA

ANOVA p<0.0001

Replication competent virus did not decline

Rasmussen et al, 2014 CROI

n=16

Immune –mediated interventions kill component

Vaccines to induce effector T cell responses

Broadly neutralising antbodies

Activators of innate immunity

Immunoregulatory interventions -PD-1 inhibitorsto reinvigorate exhausted anti HIV immune cells

Older Approaches

• Whole inactive virus – Remune

• Virus-derived gp160

• Cell-derived gp160

• Canarypox-based– ALVAC 1452

Newer Approaches

• Prime-boost (GeoVax)– HIV DNA primer

– MVA (smallpox) booster

• Vacc-4x (Bionor Immuno)

32

Therapuetic Vaccines

Novel vaccine given before exposuremay aid in viral control: SIV/macaque model

Hansen SG and Picker LJ, Nature 2013

No protection

but

Virus eradicated in 50%

Controllers (n=9)

Broadly Neutralizing Antibody

• > 30 antibodies identified

• Human studies

• VRC01: RV397/398 in acute HIV

• 3BNC117, 10-1074, PGT121

Viral clearanceCell death

Barouch DH, Nature 2013

0 20 40 60 80 100

2

3

4

5

6Viral load suppression

in macaques(n=3)

VL

log

Days after infusion

PGT121

Gene therapy to eliminate CCR5

Leukapharesis

CD4+ T-cell isolation

ZFN cutCCR5 gene

Re-infuse

Tebas P, NEJM 2014

CCR5-

CCR5+

Examples of strategies currently in human studies

SHOCKReactivating latently-

infected cellsInhibit histone deacetylase

Inhibit bromodomain extraterminalActivate toll-like receptors Activate protein kinase C

KILLViral clearance by the immune

systemBroadly neutralizing antibodies

Therapeutic HIV vaccinesAnti programmed cell

death (PD)1Anti PD ligand 1

HIV RESISTANT CELLSTransfusing cells without CCR5 gene

Gene-editing therapyBone marrow or cord blood transplantation

MINIMIZE RESERVOIRLimit reservoir with early treatment

Antiretroviral therapyBroadly neutralizing antibodies

Combination Cure

Finally-Another problemHow to measure the reservoir

Cure -conclusions

Cure aims to do one or more of the folowing

Eliminate residual Virus replication then eliminate viral replication

Enhance HIV immunity

Make cells resistant to HIV-1

Progress has been made and it is only through science experimemtation and clinical trials can this myth turn into a reality