Advances in Therapies Leading to HIV Eradication

Francesco R Simonetti, MD

Cellular and Molecular Medicine PhD ProgramJohns Hopkins University, Baltimore, MD

Advances in Therapies Leading to HIV Eradication

Francesco R Simonetti, MD

Cellular and Molecular Medicine PhD ProgramJohns Hopkins University, Baltimore, MD

FR Simonetti has no financial relationships with commercial entities to disclose

List of trials available from

o n g o in g

T o ta l= 1 1 9

O b s e r v a t io n a l s t u d ie s

T r e a t m e n t in te n s if ic a t io n / E a r ly T r e a t m e n t

C o m b in a t io n s

G e n e t h e r a p ie s

T h e r a p e u t ic v a c c in e s

A n t ib o d ie s

L a t e n c y r e v e r s in g a g e n t s

S te m c e ll t r a n s p la n t a t io n

A n t i- in f la m m a to r y / A n t if ib r o t ic

O t h e r s

Im m u n e c h e c k p o in ts in h ib ito r s

m T O R in h ib ito rs

A d o p t iv e im m u n o th e r a p y

c o m p le te d

T o ta l= 9 2o n g o in g

T o ta l= 1 1 9

O b s e r v a t io n a l s t u d ie s

T r e a t m e n t in te n s if ic a t io n / E a r ly T r e a t m e n t

C o m b in a t io n s

G e n e t h e r a p ie s

T h e r a p e u t ic v a c c in e s

A n t ib o d ie s

L a t e n c y r e v e r s in g a g e n t s

S te m c e ll t r a n s p la n t a t io n

A n t i- in f la m m a to r y / A n t if ib r o t ic

O t h e r s

Im m u n e c h e c k p o in ts in h ib ito r s

m T O R in h ib ito rs

A d o p t iv e im m u n o th e r a p y

c o m p le te d

T o ta l= 9 2

Completed Studies

Ongoing Studies

Total=119

Total=92

The landscape of current HIV Cure clinical trials

May 16, 2017

Major approaches

Infectious proviruses are stable over timeART

HIV

log 1

0cp

s/m

l pla

sma

Months Years 2-3 Weeks

t1

t2t3 t4

1

3

2

4

6

5

Cell associated HIV DNA

IUPM

Siliciano J, Nat Med 2003 Bruner K, Nature 2016

What maintains the HIV reservoir?

Mechanism Therapeutic approach

Cryptic ongoing replication • ART intensification• drug delivery• nanoparticles

Latency • Shock and Kill• Gene therapy• Lock HIV transcription

Proliferation of infected cells • Early treatment• Accelerate decay• Block clonal expansion

Evolution can be detected when HIV is not suppressed

Kearney MK, CROI 2017

Bozzi G, IAS 2016

In long-term suppressed patients, no evidence of

evolution in peripheral blood or tissues was observed

Viral replication when viremia is not suppressed

Reservoir replenishment from replication in tissues?

Lorenzo-Redondo, Nature 2016

• Viral evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream

• HIV can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy

Months on ART

3 patients, 2 fully suppressed, 1 viremic at 3 months

Rosenbloom D, BioRxiv 2017

Reservoir decay post ART initiation leads to a false evolutionary signal

What maintains the HIV reservoir?

Mechanism Therapeutic approach

Cryptic ongoing replication • ART intensification• drug delivery• nanoparticles

Latency • Shock and Kill• Gene therapy• Lock HIV transcription

Proliferation of infected cells • Early treatment• Accelerate decay• Block clonal expansion

Shock and Kill

Death by viral CPE

Death by CTL

Activation induced cell death

LRA

Limitations of current Shock and Kill strategies• Only a small fraction of proviruses is

reactivated (position effect of integration)

• Defective and intact proviruses might have a different susceptibility to latency reversal

• CTL escape mutations are common in treated chronic infection

Shock and kill strategies need to be coupled with other interventions (bNABs, DARTs, Therapeutic vaccines) to enhance reservoir clearance

What maintains the HIV reservoir?

Mechanism Therapeutic approach

Cryptic ongoing replication • ART intensification• drug delivery• nanoparticles

Latency • Shock and Kill• Gene therapy• Lock HIV transcription

Proliferation of infected cells • Early treatment• Accelerate decay• Block clonal expansion

Clonal expansion and immunological memory

ExhaustionDifferentiationMargination

Self renewalSurvival

Freq

uen

cy o

f A

g sp

ecif

ic c

ells

Time

Ag exposure Re-exposure

Infected T cell clone

Divide et Impera

• A great fraction of infected cells undergoes clonal expansion

• Expanded clones can harbor infectious proviruses

Maldarelli, 2014Wagner, 2014

Cohn, 2015

Simonetti, 2016

Simonetti FR, PNAS 2016Maldarelli F, Science 2014

Divide et Impera

• A great fraction of infected cells undergoes clonal expansion

• Expanded clones can harbor infectious proviruses

• Clonally expanded infectious proviruses are frequent in vivo

• They constitute at least 50% of the reservoir

• Can require multiple rounds of stimulation to reactivate

Maldarelli, 2014Wagner, 2014

Cohn, 2015

Simonetti, 2016

Lorenzi, 2016Bui, 2017

Hosmane, 2017

Hosmane N, JEM 2017 Lorenzi, PNAS 2016

ART

Months Years 2-3 Weeks

t1

t2t3 t4

1

3

2

4

6

5

Cell associated HIV DNA

Cognate or cross reactive

AntigenHomeostatic maintenanceIl-7 Il-15 Il-2

Integration siteDriven?

IUPM

Cell proliferation maintains HIV persistenceH

IV lo

g 10

cps/

ml p

lasm

a

Which impact of hyper acute treatment?

Ananworanich J, CROI 2017

Median rebound 14 days

Median rebound 22 days

• HIV-DNA pre-ATI undetectable• TILDA <1.4 tat/rev RNA+ cells/106 CD4 pre-ATI• Pre-ATI, median CD4 was 561 cells/ul

Study RV254 n=8 participants treated during Fiebig I for a median of 2.8 years

Hyper-acute treatment alone did not impact time to rebound

Ananworanich J, CROI 2017

Weeks after treatment interruption

• CD4 change post-ATI -87 to 39 cells/ul• HID-DNA levels >6 months went back to pre-ATI levels

• CD4/CD8 ratio < 1 correlated with time to rebound• HIV-specific CD8 increased post ATI and correlated with viral load

Median rebound in 26 days (range 13-48)

Early treatment does not prevent HIV clonal expansion

Hughes S, CROI 2017

Additional patients in Fiebig I/II are under investigation

5 out of 8 subjects had detectable clones pre-ART

6 out of 6 subjects had detectable clones post-ART

Viral control induced by HIVcons vaccine in early treated individuals

Mothe et al, BCN02 trial, CROI 2017

Viral control can be achieved by redirecting CTL against conserved HIV regions in the context of retained T-cell function and a reservoir with reduced size and diversity

ChAd+MVA+Romidepsin induced CD8-mediated responses to otherwise subdominant conserved epitopes.

Post treatment control in 40% of the participants

Going Beyond N=1

Hill, PNAS 2014

• Interventions need to reduce the HIV reservoir at least by 4 logs to impact duration of ART-free remission

• Timothy Brown has been in remission for 10 years!

• In this context allogeneic transplant represents one of the best models to study eradicative approaches

Open questions:• Which role has graft versus host disease in the elimination of infected cells?

• Which conditioning and transplant regimen can maximize the reservoir reduction?

• Is CCR5∆32/∆32 status necessary for remission?

Donor Conditioning regimen

Transplant Chimera GVHD HIV DNAcp/106

PBMC

HIV RNA in plasmacp/ml

qVOAIUPM

HIV DNA in ileum biopsy

WT/WT Myoablative Cord blood +HLA mismatched

incomplete NO 25 5 0.034 -

∆32/∆32 Reduced intensity

HLA-matchedunrelated

full YES <LOD <LOD <LOD positive

WT/WT Reduced intensity

HLA-matched sibling

full YES <LOD <LOD <LOD <LOD

Wensing, ECCMID 2017

The “graft versus HIV reservoir effect” may contribute to the clearance of the reservoir

Reservoir reduction is independent of donor CCR5 genotype

Long-term follow up post SCT in three patients

Reservoir recrudescence post stem-cell transplant

Wensing, ECCMID 2017

• No switch in HIV tropism or ongoing replication• Failed engraftment and lymphopenia can lead to the

replenishment of the reservoir due to massive homeostatic expansion of recipient infected cells

HIV Latency or Immune control? The Mayo Patient

Cummins, CROI 2017

• 55 yo, B-lineage acute lymphoblastic leukemia

• Reduced intensity conditioning followed by a HLA-matched, CCR5 WT, related-donor

• Developed colon biopsy proven grade 1 GVHD

Western Blot

288-days drug-free remission post transplant

Cummins, CROI 2017

HP: immune activation in the setting of GVHD without anti-HIV immunity may cause homeostatic proliferation of latently infected cells

However, no increase in HIV DNA was observed during drug free remission!

At day 288 of the ATI, asymptomatic viral rebound occurred at 60 cp/ml, then rose up to 1640, necessitating re-institution of cART

Future Directions

• Gene therapy – CRISPR Cas9• Cell lines• Animal Models• Limited delivery

• ABX464 – Targeting HIV mRNA biogenesis • 004 Phase II Clinical Trial

• 40% DNA reduction in responders• No difference in rebound

• IAS 2017 Paris• 005 GALT reservoir

• VEDOLIZUMAB (Anti Alpha4 Beta7)• Phase 1 currently recruiting (NIAID)• Phase 2 not yet recruiting (Ottawa)

Conclusions

• Clonal Expansion is a major mechanism of persistence and a barrier for HIV cure

• Early treatment alone is not sufficient to increase the chance of post-treatment control

• Bone marrow transplant can help us understand latency, reservoir stability and eradicative potential

• New strategies are in development, both in pre- and clinical phases

1990s 2006

2017 20XX

Acknowledgments

University of Pittsburgh

John W MellorsMichele Sobolewski

Melissa TosianoDianne Koons

Lou Halvas

HIV Dynamics and Replication ProgramFrank Maldarelli

John M CoffinElizabeth M Anderson

Stephen Hughes

University of MilanClaudia BalottaPaolo Cattaneo

Alessia Lai Giorgio Bozzi

Annalisa BergnaFrancesca Binda

Johns Hopkins UniversityRobert F SilicianoJanet D Siliciano

Ya-Chi HoCMM Program

“Since I had the vaccine, I haven’t had to take any pills or meds for six months.”

“It is not a complete cure, everything is fine, I am thrilled, but I am always expecting the worst.”

Thanks to study participants

BCN-02 trial volunteer

fsimonetti@jhmi.edu