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Situación actual de la posibilidad de erradicación del VIH

Santiago Moreno

Hospital Ramón y Cajal Universidad de Alcalá

Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

6º Congreso de Sogaisida

(2)

The end of AIDS?

prevention cure

seek,

(3)

¿Cuáles son las

barreras

para la

(4)

HIV RNA CD4 cou nt 50 Years on cART 0 off cART 1

Rapido rebote del virus

(5)

HIV RNA CD4 cou nt 50 Siempre se detecta

DNA HIV en las células infectadas

Years on HAART

0 1

HIV DNA

(6)

HIV RNA CD4 cou nt 50 No parece existir

la “carga viral indetectable”

Years on HAART

0 1

HIV DNA

1

(7)

7

¿Por qué el VIH no es erradicable?

Rebrote tras la suspensión del TAR

Reservorios celulares Replicación persistente Reservorios anatómicos

(8)

Replicación Vírica Residual

HAART

(9)

Anatomical reservoirs

HAART HAART

(10)
(11)

GI tract is a significant viral reservoir on cART

Chun et al., J Infect Dis 2008; 197:714; Yukl et al., J Infect Dis 2010 (in press)

N=8, time on HAART with undetectable HIV RNA 2.8 – 12 years

HIV DNA Copi es per millio n cell s

(12)

Variable penetration of ARV in tissue

(13)

HIV latency and infection of resting T-cells

Activated CD4+ T-cell

Resting CD4+ T-cell

cART

Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med2006; 203:865; Saleh et al., Blood 2007;

110:416; Marini et al., J Immunol2008; 181: 7713-20; Bosque and Planelle, Blood 2009; 113:58; Cameron et al., Proc Natl Acad Sci 2010; 107(39):16934

Tissue chemokines

(14)

Eliminate latently infected T-cells: activate latent HIV

Activated CD4+ T-cell

Resting CD4+ T-cell

(15)

La infección latente puede

establecer en muchas células T

Thymus Peripheral circulation

M M M M Effector/ transitional Central memory Ag Central memory Bone marrow

Chun et al., Nature 1997; 387:183; Finzi et al., Science1997; 278:1295; Brooks et al., Nat Med 2001; 7:459 ;

Chomont et al., Nat Med2009; 15: 893; Dai et al., J Virol 2009: 83(9):4528-37; Carter et al., Nat Med 2010; 16: 446; Wightman et al., J Infect Dis 2010 (in press)

Naïve T cells Transitional memory

Multipotent progenitor cells

Latent reservoir

(16)

Maintenance of HIV latency

Survival (long half-life)

1.

Repressed transcription

e.g., acetylation,  methylation, transcriptional interference Homeostatic proliferation 2. Homeostatic proliferation e.g., IL-7 activation 3. Negative

regulators Negative regulators of

T-cell activation e.g., PD-1

(17)

0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000 10000 0 1 2 3 4 5 6 7 8

Time on treatment (years)

Freq

uen

cy

(IUPM)

Stability of latently infected T cells

-t ½ = 44.2 months 73.4 years

(18)

current clinical trials:

eliminate

latently

(19)

Activating latent HIV infection: rationale HIV DNA HIV US RNA HIV DNA HIV proteins HIV virions Latent infection “activate” Cell death

(20)
(21)

Activating latent HIV: in vitro  Histone deacetylase (HDAC) inhibitors1, 2  Cytokines – IL-73,4 – IL-155  Anti-alcohol agent – Disulfiram6  Methylation inhibitors – 5-aza-dC7  Immune modulation – Anti PD1  NF-kB activators – Prostratin, PMA, TNF4  Akt/HEXIM-1 modulators – HMBA8  Histone Methyltransferase inhibitors (HMTI)9 – Chaetocin, BIX-01294  Other – Quinolines10  Combination enhances potency4,9,11

1Contreras, J Biol Chem. 2009;284(11):6782-9; 2Wightman., Immunol Cell Biol 2012; 3Wang, J Clin Invest 2005; 115:128; 4Saleh, Retrovirology 2011;8:80;5Chomont, 6thIAS Rome 2011; 6Xing, J Virol; 2011;85(12):6060-4;

7Friedman, J Virol;2011 85:9078-8; 8Contreras PLoS Pathog. 2007 3(10):1459-69 ; 466-72; 9Bouchat, AIDS 2012; 10Xing et al., J Antimicrob Chemother. 2012;67(2):398-403; 11Reuse et al., PLos One 2009;4:e6093

  

(22)

Vorinostat activates HIV transcription in vivo

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 Rel ative HIV -1 gag RNA cop ies 100 Pt 7 Pt 8

(23)

The effect of multidose vorinostat * * 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

(24)

Fold change in unspliced HIV RNA 0 10 20 30 40 VOR021 VOR006 VOR003 VOR022 VOR001 VOR019 VOR010 VOR008 VOR004 VOR014 VOR023 VOR013 VOR017 VOR009 VOR018 VOR020 VOR016 VOR011 VOR015 VOR002

fold change max fold change d84

Fold increase CA-US HIV RNA above baseline

(25)

GEE analysis grouping all “on drug” and “post drug” data points and adjusting for CV of the assay

Significant increase in unspliced HIV RNA on and post drug

Mean fold increase in US HIV RNA

Pre to on treatment = 2.65 (95% CI 1.76, 3.52, p=0.023) Pre to off treatment = 3.00 (95% CI 2.16, 3.84, p=0.018)

(26)
(27)

Non activating LRAs do not induce

(28)

Some LRA combinations are very effective in patient cells

(29)

Reducción del reservorio necesaria para lograr la curación

(30)

Do cells die following activation of latent infection? HIV DNA Latent infection “activate” Cell death

?

(31)

Vorinostat stimulated cells don’t die in vitro

(32)

Vorinostat-activated cells only die in vitro in the presence of CTL

Shan et al., Immunity 2012; 36:1-11 In vitro model of latent infection that over expresses BCL-2

(33)

Increase immune clearance HIV DNA Latent infection “activate” Cell death

?

“kill” therapeutic vaccine Anti-PD1 or anti-PDL-1

(34)

Anti PD-1 or anti PDL-1: “double hit”

Other advantages

 Anti PD-1 boosts

HIV-specific immunity

 Recent clinical trials of

anti PD-1 and anti PDL-1

(BMS) in malignancy

Clinical trials for HIV cure

•ACTG5301 (anti PD-1, Merck)

– Single IV dose of MK3475 at dose of 0.1, 1, 3, or 10 mg/kg – HIV+, CD4>350 (n=40)

•ACTG (anti PDL-1; BMS), approved

PD-1 PDL-1 Suppresses T-cell activation activation PDL-1 Anti-PD-1 blocking Ab

(35)

current

strategies

aimed at cure

(36)

HIV eradication: cure or remission

Cure Remission

Infectious Diseases model Cancer model

Elimination of all HIV-infected cells

Long term health in absence of cART

HIV RNA < 1 copy/ml HIV RNA < 50 copies/ml

(37)
(38)

Sterilising cure: lessons learned

(39)

Sterilising cure: lessons learned

 Latently infected cells can be eliminated

 Complete viral suppression without cART is possible

Hutter et al., N Engl J Med, 2009; 360:692; Allers et al., Blood. 2010 117(10):2791; 102 103 104 105 106 107 HIV -1 RNA (c op y /mL) cART cART AML diagnosis 2 nd bone marrow transplantation Bone marrow transplantation 2007 2008 2012 GI tract biopsy CSF Brain biopsy 2009 GI tract biopsy RNA/DNA

(40)

cART HIV+ Leukemia (AML) Stem cell transplant (X2) Donor CCR5– (DD32) Chemotherapy (x4) Total-body irradiation (x2)

What “cured” Timothy Brown?

CCR5+ (WT) “CCR5–” off cART no viral rebound “sterilising cure” Graft vs host disease

?

?

?

?

?

(41)

Henrich et al., J Infect Dis 2013; 207: 1694-702; Henrich et al., 8thIAS Conference, Kuala Lumpur, July 2013

The Boston patients: allogeneic transplantation

HIV+

Lymphoma

CCR5+

(heterozygous)

HIV DNA neg IUPM neg (2-4 yrs post Tx) Allogeneic BMT CCR5+ (WT) cART

Reduced intensity conditioning (RISC) HIV RNA neg (8-15 weeks post ATI)

(42)

IUPM <0.01 IU per 10E6 CD4+ T-cells

Rectal Biopsy DNA neg HIV Antibody negative

Henrich et al., J Infect Dis 2013: 207(11):1694-702; Henrich et al, 8th IAS Conference , Kuala Lumpur, July, 2013

The Boston patients

IUPM <0.01 IU per 10E6 CD4+ T-cells

A.

(43)

Estrategias para la curación. Transplante de médula ósea

Henrich T et al.. HIV-1 Rebound Following Allogeneic Stem Cell Transplantation and Treatment Interruption. 21th CROI. Boston, 3 – 6 Marzo 2014. #144LB Cinética de repunte de carga viral en los dos pacientes de Boston que recibieron

(44)

Functional cure: elite controllers

 Strong HIV-specific T-cell

responses

 HLA-B-viral peptide

interactions critical

 Long term effects

– Loss of CD4 (7%)

– Ongoing virus replication and

evolution

– Immune activation increased

Hunt et al., J Infect Dis 2008 ;197:126; Hatano et al., J Virol 2009; 83: 329; Pereyra et al., J Infect Dis

2009; 200:984; HIV Controller Study, Science. 2010;330(6010):1551-7 Soghoian DZ et al., Sci Transl Med2012; 4(123):123ra25; Hersberger et al., Blood. 2011;117(14):3799-808

Long term non-progressors

Elite

(45)

Functional cure: post cART controllers

Hocqueloux et al., AIDS 2010; Saez-Cirion et al Plos Pathogens 2013; 9(3):e1003211

VISCONTI cohort; n=14, treated in acute infection; median time since treatment interruption 9 years

Year 01 02 03 04 05 06 07 08 09 10 CD4+ T c ells /mm3 0 500 1000 1500 2000 RN A copies/ml 100 101 102 103 104 105 106 107 108 109 VisORA02

(46)

The Mississippi baby

(47)

The Mississippi baby

(48)

Gene therapy to eliminate CCR5:

Sangamo Biosciences Inc, SB728-902

SB728-902

Lalezari et al., 18th CROI, Boston, Feb 2011

SB728-T

n=6

Aviremic patients on cART CD4>450

Treatment interruption

(49)

Gene therapy to eliminate CCR5

Leukapharesis CD4+ T-cell isolation

ZFN modification of CCR5

Re-infuse Safe and well tolerated

CCR5 modified cells persist 1-6% in blood at 24 weeks

Detected in tissue Lalezari et al., 18th CROI, Boston, 2011

Inclusion criteria n

NCT01044564

(PI Tang, Sangamo; 5 cohorts)

Dose escalation 3 x 3

cART failure 4

CCR5D32 hetero 20*

NCT00842634

(PI Tebas, Sangamo; 3 cohorts)

cART failure 6

Stable cART 6*

Poor CD4 recovery 6

NCT01252641 (PI Tang, Sangamo)

No cART 30

(50)

Reduced viral set point

(51)

What can we learn from these sporadic cases of cure?

 The reservoir can be eliminated in some patients

 Long term “control” of virus replication in the absence of ART is possible

 Very early ART likely limits the size and or distribution of latently infected cells. Unclear how common this occurs.

 Need to translate these lessons to feasible and scalable interventions

(52)

References

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