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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