Inmunoteràpia per la prevenció I tractament de la infecció pel VIHBeatriz Mothe, MD, PhD

HIV Unit, Infectious Diseases Department. IrsiCaixa AIDS Research Institute

Hospital Germans Trias i Pujol, Badalona.

XXVIII Jornades de la Societat Catalana de Malalties Infeccioses i Microbiologia Clínica

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• Basics in immunology• What’s new in prevention?• Are we closer to an HIV cure?

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Infectious Disease vs Immune Disease of a viral origin

⬆ Viral escape to CTLsProgressive exhaustion of CTLs:

⬇Effector Functions⬇ Proliferation Capacity

4 SCMIMC_20191026CD8

TLRsNLRCLRsRLRs

PRR:

FcRsTCR

Cytokines

Antigen presentation

Fc

Cell

NeutralizationBlocking

Antibody-dependent cellular cytotoxicity(ADCC)

Antibody-Dependent Cellular Phagocytosis(ADCP)

Cell lysis mediated by complement SCMIMC_20191026Courtesy J. Carrillo

bNAbs functions (not only block!)

Infected cell

Infected cell

ViralPeptides

(epitopes)

HLAClass Ialleles

CD8

T cellReceptor

Antiviralcytokines

and lytic granules

Adapted from B.Walker

CTL Killing

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T cells are not alone : Immunological synapse

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Immunotherapies for cancer

https://cincodias.elpais.com/cincodias/2018/03/12/companias/1520881368_939672.html SCMIMC_20191026

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Preventive Strategies Cure Strategies• Avoid HIV acquisition after exposure, but• If infection occurs

- to limit its spread - enable HIV control- avoid progression- limit transmission to others

• Achieve complete elimination of HIV• If HIV persists

- enhable HIV control- avoid progression- limit transmission to othersO

BJEC

TIVE

S

• bNAbs to block/neutralize virions• T cells to eliminate infected cells

• Reactivate viral reservoir (Kick & Kill)• T cells to eliminate infected cells

ACTO

RS

• ‘HEALTHY’ Immune system• Need to tackle huge HIV diversity worldwide

• ‘UN-HEALTHY’ & Exhausted Immune system• Pre-existing non-efficacious responses• Ability of the virus to escape to CTL pressureHO

STImmunotherapies in HIV

9 SCMIMC_20191026

Preventive Strategies Cure Strategies• Avoid HIV acquisition after exposure, but• If infection occurs

- to limit its spread - enable HIV control- avoid progression- limit transmission to others

• Achieve complete elimination of HIV• If HIV persists

- enhable HIV control- avoid progression- limit transmission to othersO

BJEC

TIVE

S

• bNAbs to block/neutralize virions• T cells to eliminate infected cells

• Reactivate viral reservoir (Kick & Kill)• T cells to eliminate infected cells

ACTO

RS

• ‘HEALTHY’ Immune system• Need to tackle huge HIV diversity worldwide

• ‘UN-HEALTHY’ & Exhausted Immune system• Pre-existing non-efficacious responses• Ability of the virus to escape to CTL pressureHO

ST

1 Main hurdles for preventive vaccines

Huge global viral diversity

All HIV-1 subtypes, sub-subtypes, CRF

HIV-infected patient

One HIV-1 subtype

Annual global Influenza A

Adapted from McCutchan F. and Korber B., Brit Med Bull 2001; Hemelear 2004, WHO/UNAIDS10 SCMIMC_20191026

ABCDF, G, H, J, KCRF01_AE

other

CRF02_AGCRF03_AB

Subtype

HIV genomes differ by 10-30% whilstsHuman genomes differ by about 0.1%

1 Main hurdles for preventive vaccines

Low ammount of envelope spikes / virionAccess to binding sites due to sugar shield

11 SCMIMC_20191026Schiller 2014

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Several bNAbs already in NHP or clinical testing

Sok, Burton 2019 Passive administration!!

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First preventive vax with a positive (weak) Efficacy signalThai trial

16,000 HIV negs>3y follow-up$$$$$$$$$$$$$

Phase III

1

Rerks-Ngarm NEJM 2009, Haynes B, NEJM 2012

RV144 ‘Thai’ Trial (2009)

low risk population

First preventive vax with a positive (weak) Efficacy signalThai trial

Phase III

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1

Barouch, Lancet HIV 201815 SCMIMC_20191026

Since then, only 1 trial into Phase IIIMOSAICO / HVTN 706

Phase III

1

Protection through both Ab & CTL

Barouch, Lancet HIV 2018

Since then, 1 trial into Phase IIIMOSAICO / HVTN 706

Fase IIB : ongoing Sudafrica, 2600 women (IMBOKODO) Fase III EU, USA, Latinamerica (2019, 3800, MOSAICO) Expected efficacy data 2023

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Phase III

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Not sterilizing but induction of control post-infection

• Interventions studies in the SIV model suggests post-intervention control is attainable- CMV-vectored vaccines inducing 50% of control after infection

• However, mechanisms are also quite unclear and a CMV intervention difficult to translate into humans

Hansen 2011/2013

CMV-vectored vaccines suggest role of MHC class II & HLA-E restricted responses

SCMIMC_20191026

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Preventive Strategies Cure Strategies• Avoid HIV acquisition after exposure, but• If infection occurs

- to limit its spread - enable HIV control- avoid progression- limit transmission to others

• Achieve complete elimination of HIV• If HIV persists

- enhable HIV control- avoid progression- limit transmission to othersO

BJEC

TIVE

S

• bNAbs to block/neutralize virions• T cells to eliminate infected cells

• Reactivate viral reservoir (Kick & Kill)• T cells to eliminate infected cells

ACTO

RS

• ‘HEALTHY’ Immune system• Need to tackle huge HIV diversity worldwide

• ‘UN-HEALTHY’ & Exhausted Immune system• Pre-existing non-efficacious responses• Ability of the virus to escape to CTL pressureHO

ST

ART does not cure HIV

No new transmissions

ART

Circ

ulat

ing

Viru

s

Limit of detection

TimeVIRAL RESERVOIR

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T cell vaccines as the backbone of any HIV cure strategy‘We aim to eliminate HIV infected cells. And this is what CTL do’

SCMIMC_20191026

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T cell vaccines as the backbone of any HIV cure strategy

LRA Vaccine

Vaccines+ ’Reactivators’ of the viral reservoir

Vaccines aloneIn early-treated individualsw/ new vaccine candidates

Vaccines + Immunotherapies to • improve CTL functionality, • enhance CD4 T help, • ADCC, etc

‘Personalized’ strategies

SCMIMC_20191026

22 Years

pVL

CD4

pVL

CD4

pVL

CD4

Spontaneous Control(EC/VC)

Post-intervention Control??

Post-Treatment Controllers

?

Which T cell immune Response? Models of HIV control

SCMIMC_20191026

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Years

pVL

CD4

pVL

CD4

pVL

CD4

• Lower peak viremia • Less symptomatic ARS

• Maintain suppressed viremia without ART• Able to mantain low levels of reservoir• Usually do not transmit (but potentially could)

Leon 2016, Blankson 2007, O’Conell 2010, Ostrowski 2008, Hunt 2008, Pereyra 2009, Pereyra 2012, Crowel 2016, Li 2019, Avettand-Fenoel 2019

BUT• Can progress / lose control (up to 35%?)

• Generally harbor replication competent virus and haveevidence of ongoing viral replication and evolution

• Higher levels of immune activation and inflamation comparedto ART-suppressed

• Higher incidence of non-AIDS related diseases (CV)

• Higher all-cause hospitalizations

• Non-sterilizing immunity Can be superinfected by HIV

Not a perfect model!

Spontaneous HIV control (EC / VC / LTNP)

SCMIMC_20191026

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Combined mechanisms of Spontaneous HIV control

HOST

VIRUS IMMUNE RESPONSE

HLA-BDelta-32 CCR5rs 9039999 SNP in the HLA C

HETEROGENEOUS GROUP

SCMIMC_20191026

• GWAS studies with signal in Chromosome 6 (HLA genes) associated with EC

• Class I loci (HLA-A, -B and -C) associated with HIV control

25 Fellay, 2007; O’Brien 2001; Rosas-Umbert 2018

Host - HLA

SCMIMC_20191026

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Characteristics of T cell responses in controllers

LANL SCMIMC_20191026

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CTL specificity matters

Frahm 2004, Zuñiga 2006, Betts 2006, Mothe 2011, Mothe 2015

• Relative Gag dominance

• Several specific HIV targets enriched in

controllers in Gag, but also in Pol, Vif & Nef

• Not only if Good HLA! base of HTI vaccine

CTL immune screens in >1000 HIV+

Time (years)

pVL

CD4

pVL

CD4

pVL

CD4

SCMIMC_20191026

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Functionality

Betts 2006, Julg 2010, Saéz-Cirion 2007, Chen 2009, Hanckok 2015, Pereyra 2014; Mothe 2019

• Polyfunctionality of T-cells

• Maintain high viral inhibition capacity by CD8

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29 Hocini 2019

Gene expression in controllers

• Up regulation of T-cell activation gene expression

• Low inflammation

• Down modulation of NK inhibitory cell signaling

Role of NK function?

SCMIMC_20191026

30 Okulicz 2009, Leon 2016, Pernas 2018, Rosas-Umbert 2018

What do we know about losing HIV control (LoC Critical for the longevity of vaccine-induced response!

N=14 ‘losers’

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LoC associated with increased activation and exhaustion

Rosas-Umbert 2018

• Same HLA as long-term EC/VC

• Change to CXCR4 viruses after LoC in few individuals

• Only 1 case of superinfection

• No evidence of increased CTL escape by viral sequencing Pre-Post LoC

• No loss of Gag dominance

SCMIMC_20191026

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LoC preceeded by a lower suppressive capacity

Rosas-Umbert 2018, Koofhethile 2016 SCMIMC_20191026

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Post-Treatment controllers (PTC)

• After first isolated reports first group – the VISCONTI Cohort (n=14) in early-treated individuals (NOT ACUTE)

• CHAMP Metaanalysis of 700 ATI patients from – 67 PTC

• <13% early-cART (within 6 months from acquisition) & <4% in Chronic-treated

Salgado 2011, Saez-Cirion 2013, Sneller 2018, Namazi 2018

‘Non-rebounders’ ‘Post-rebound controllers’

Up to 30%

SCMIMC_20191026

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Post-Treatment controllers (PTC)• Mechanisms still unclear BUT seems to be different from ‘classical’ spontaneous

controllers:

• Not enriched in Beneficial HLA alleles for suppressive CTL response ( B35)• Have history of high viral loads before ART or during previous ATI • Not show ‘classical’ strong CD8 T cells Polyfunctional HIV-specific CD4 T

cells (closer to Early-treated rather than controllers)

• Are also able to maintain low reservoir levels different cell subsets?

Salgado 2011, Saez-Cirion 2013, Samri 2016

CD4

CD8

SCMIMC_20191026

35 Years

pVL

CD4

pVL

CD4

pVL

CD4

Spontaneous Control(EC/VC)

Post-intervention Control??

Post-Treatment Controllers

?

Post-Intervention control?

SCMIMC_20191026

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Post-Intervention controllers ??- Therapeutic Vaccines + TLR7 agonist in ART-treated (acute) CD8 responses associated with lower setpoint

and delayed rebound

Borducci 2016, Borducci 2018

- TLR7 agonist + PGT 121 bNAb in ART-treated (acute) CD8 depletion rise pVL ONLY in post-rebound controllers (≄ mechanisms!)

SCMIMC_20191026

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- Combination of 10-1074 + 3BNC117 in acute infection (no ART) CD8 mediated without ‘classical’ controller phenotype probable role of CD4 T help Preserve functional initial CD8 T cell response to limit reservoir seeding

Nishimura 2017 SCMIMC_20191026

Post-Intervention controllers ??

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- BCN02 Kick&Kill CT in early-treated individuals

MVA1 MVA2RMD1-3 Monitored Antiretroviral Pause (MAP) cART Ressumption Phase

-4 01

3 4 5 6 910 13 17 +4wk +12wk

+24wkweeks>2,000 cp/ml

(x2)

MAP1-32

Mothe & Rosas-Umbert, submitted 2019 SCMIMC_20191026

Post-Intervention controllers ??LRA Vaccine

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Additional effect of ICB?

- Vaccine-induced responses in early-treated can be increased in vitro by ICB

Marin, Garcia-Prado, unpublished

ChronicChro (n=11)

Early treated vaccinatedEtVac (n=11)

Early treatedEt (n=12)

HIV-1 infected individuals

HIV-1 Gag peptide poolHIV-1 vaccine peptide pool

Proliferation (CFSE-)IFN-production

HLADR+/38+

Isotype PD-1 TIM-3α α

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Additional effect of ICB?

Marin, Garcia-Prado, unpublished

Proliferation

IFNg

Activation

- Impact of αPD-1 and αTIM3 in HIV-1 specific-CD8+ T cell responses in ET-Vac& Chro (not in ET alone!)

SCMIMC_20191026

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26 beneficial HIV targets

Time (years)

HIV pVL

CD4

pVL

CD4

pVL

CD4

Mothe JTM 2011; Mothe Plos ONE 2012

New therapeutic vaccinesBased on natural HIV control (HTI)

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1

Phase I/II: ongoing at Can Ruti (n=45: 30 Vax + 15 Pbo) Early_treated Phase II: Vax + TLR7 agonist, multisite. Expectes start Q1 2020

RESULTS EXPECTED 2020/2022 . AELIX THERAPEUTICS

New therapeutic vaccinesBased on natural HIV control (HTI)

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TAKE-HOME messages

• HIV/AIDS as an immune disease

• World wide diversity and ability to escape the immune pressure as main hurdles.

• Need to build on a non-efficacious pre-existing immune response to HIV bypassing the immunosuppressive status

• Need to either re-direct/educate this previously inefficient response (shift CTL immunodominance patterns) &/or

induce novel specificities all together ,

• Need to improve functionality of T-cells (killing) and make it long-lasting!

• Need to tackle CTL-driven escape capacity (already contained in most proviruses in Chro)

• CD8 CTL do not work alone! Require helper CD4 T cells & a non-exhausted environment Immunotherapies

• T cell vaccines as the backbone of any prevention and HIV cure strategy

SCMIMC_20191026

bNAbs + T cell vaccines

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LRA Vaccine

T cell vaccines+ ’Reactivators’ of the viral reservoir

T cell Vaccines aloneIn early-treated individualsw/ new vaccine candidates

T cell Vaccines + Immunotherapies to • improve CTL functionality, • enhance CD4 T help, • ADCC, etc

Preventive Strategies

Cure Strategies

Cure Strategies

Cure Strategies

SCMIMC_20191026

Jose MoltóLucía BailónMiriam LópezCristina MirandaPatricia CobarsíJessica ToroRoser Escrig

BRANDER LABChristian BranderMiriam Rosas-UmbertMarta Ruiz-RiolAnuska LlanoSamandhy CedeñoBruna OriolSandra SilvaAlex OlveraClara DuranLuis Romero

Javier Martinez-PicadoM. Carmen PuertasAngel BayonSara Morón-López

Julia Garcia-PradoMiguel MarínAlba Ruiz

Roger ParedesBonaventura Clotet

ALL STUDY PARTICIPANTS!!!