Ezequiel Ruiz-Mateos Carmona

U.G. Clínica Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva

Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS)

Servicio Andaluz de Salud “Programa Nicolás Monardes”

GESIDA 2019 – TOLEDO, DICIEMBRE 2019

THE ROLE OF IMMUNOMETABOLISM IN THE PERSISTENT

SPONTANEOUS CONTROL OF HIV INFECTIONGeSIDA2019

1000

500

750

100

200

CD

4+

T-ce

ll/m

m3

50

0

PI CHRONIC INFECTION AIDS

Weeks Years Months/years

THE NATURAL COURSE OF HIV INFECTION

106

104

105

102

103

Log H

IV R

NA

cop

ies/m

L

T-CD4+

HIV Viremia

GeSIDA2019

nº

CD

4+ /

µL

PI AIDS

106

104

105

102

103

T-CD4+ (variable)

Viremia ( < 50 cop/ml)

YEARS

HIV “Elite”

Controller

(<1%)

1000

500

750

100

200

050

«HIV ELITE CONTROLLERS»

• Making difficult the identification of the biological mechanisms underlying these phenotypes in cross-sectional studies.

Heterogeneous phenotype

- More than ten different definitions in the literature. (Olson et al. PloS one 2014)

- Dynamic phenotype

Log H

IV-1

cop

/mL

GeSIDA2019

WHEN DOES HIV CONTROL START?

1982

nº

CD

4+ /

µL

PI AIDS

106

104

105

102

103

T-CD4+ (variable)

YEARS

HIV “Elite”

Controller

(<1%)

1000

500

750

100

200

050

≈ 17 moths*

*Madec et al. AIDS 2013

• Just after seroconversion

• Although for 25% of subjects it took more than three years

aprox. 20 years

Log H

IV-1

cop

/mL

GeSIDA2019

nº

CD

4+/µ

L

T-CD4+

Viremia

YEARS

Virological

progression

1000

500

750

100

200

500

250

150

200

50

100

1 2 3 4 5 6

cART

Adapted from Leon et al AIDS 2016

IS THE HIV CONTROLLER STATUS UNLIMITED ON TIME?

Lo

g H

IV-1

co

p/m

L

nº

CD

4+/µ

L

T-CD4+

Viremia

YEARS

Immunological

progression

1000

500

750

100

200

500

250

150

200

50

100

5 10 15 20

cART

Lo

g H

IV-1

co

p/m

L

GeSIDA2019

V

iro

lo

g

ic

a

l P

ro

g

re

s

s

io

n

Im

m

u

n

o

lo

g

ic

a

l P

ro

g

re

s

s

io

n

C

lin

ic

a

l P

ro

g

re

s

s

io

n

0

2 0

4 0

6 0

8 0

1 0 0

%

HI

V

co

nt

ro

ll

er

s

V

iro

lo

g

ic

a

l P

ro

g

re

s

s

io

n

Im

m

u

n

o

lo

g

ic

a

l P

ro

g

re

s

s

io

n

C

lin

ic

a

l P

ro

g

re

s

s

io

n

0

2 0

4 0

6 0

8 0

1 0 0

%

HI

V

co

nt

ro

ll

er

s

Virological prog.

Immunological prog.

Clinical prog.

23.5

44.1

3.462.5 38.9

Rate of progression in HIV-1 controllers

Leon et al AIDS 2016

RATES OF PROGRESSION IN HIV-CONTROLLERS

n=204

Combined endponint= 53%

GeSIDA2019

ELITE CONTROLLERS: HETEROGENEOUS AND DYNAMIC PHENOTYPE

TransientElite

Controller

YEARSPI AIDS

¡Importancia de los estudios longitudinales!

Permiten conocer factores asociados a la pérdida de control

Estudios transversales: Heterogeneidad en el paciente controlador

PersistentElite

Controller

YEARSPI AIDS

GeSIDA2019

FACTORS ASSOCIATED TO PERSISTENT CONTROL

TRANSIENT Cont. (TC) PERSISTENT Cont. (PC)

Pernas et al. J Virol 2018

EC-GeSIDA2019

- IMMUNOLOGICAL FACTORS

Pernas, Tarancón-Diez et al. J Virol 2018

3 functionsProduction of intracelular INF-γ, TNF-α e IL2

CTCP

pIN

DE

X(3

fu

nct

ion

s)

CT

FACTORS ASSOCIATED TO PERSISTENT CONTROL%

pati

en

tsw

ith

Gag

-sp

ecif

ic

CD

4+

T-c

ell

resp

on

se

GeSIDA2019

- VIROLOGICAL FACTORS

100

3976

35

45

99

99

0.01

0.01

100

0.01

89

86

47

40

0.01

100

0.01

99

64

66

0.01

TRANSIENT CONTROLLER (TC)

PERSISTENTCONTROLLER (PC)

Pernas, Tarancón-Díez et al. J Virol 2018

: Análisis de diversidad viral en cuasiespecies virales

FACTORS ASSOCIATED TO PERSISTENT CONTROL

GeSIDA2019

Virus genetic diversity

Polifunctionality

Pernas, Tarancón-Díez et al. J Virol 2018

FACTORS ASSOCIATED TO PERSISTENT CONTROL

GeSIDA2019

Pernas, Tarancon-Diez et al. J Virol 2018

Cytokines array

FACTORS ASSOCIATED TO PERSISTENT CONTROL: LOW INFLAMMATION

GeSIDA2019

Rodriguez-Gallego, Tarancon-Diez et al. J Infect Dis 2018

FACTORS ASSOCIATED TO PERSISTENT CONTROL: PROTEOMIC PROFILE

GeSIDA2019

Rodriguez-Gallego, Tarancon-Diez et al. J Infect Dis 2018

FA11, Coagulation factor XI

AACT, α-1-antichymotrypsin

FCN2, Ficolin-2

LG3BP, Galectin-3-binding protein

1433Z, 14-3-3 proteinzeta/delta

FACTORS ASSOCIATED TO PERSISTENT CONTROL: PROTEOMIC PROFILE

GeSIDA2019

Tarancon-Diez et al. Ebiomedicine 2019

FACTORS ASSOCIATED TO PERSISTENT CONTROL: METABOLOMIC PROFILE

GeSIDA2019

“Aerobic Glycolisis”

- Mitochondrial Dysfunction

- Oxidative Stress

Fatty Ac. Synthesis

- “Warburg Effect”

Branched Aas

Tarancon-Diez et al. Ebiomedicine 2019

FACTORS ASSOCIATED TO PERSISTENT CONTROL: METABOLOMIC PROFILE

GeSIDA2019

The metabolomic profile is associated with HIV-specific T-cell response

Tarancon-Diez et al. Ebiomedicine 2019

FACTORS ASSOCIATED TO PERSISTENT CONTROL: IMMUNEMETABOLISM

GeSIDA2019

INMUNOPATHOGENESIS AND ADAPTATIVE INMUNOMETABOLISM : T-CELL

Van der Heiden et al. Science 2009 Pierce et al. Science 2013

GeSIDA2019

Metabolic pathways that support cell growth and proliferation

Pierce et al. Science 2013

Warburg effect: Increaseanabolic pathwaysGeSIDA2019

Metabolic pathways that support cell growth and proliferation

Pierce et al. Science 2013

Citrate: Fuels fatty acidsynthesis. Increase thesize of ER, Golgi andmembrane.

NO: High concentrationswith Warburg effect.Inhibition of ETC.

Anabolic metabolismInmunogenic

Pro-inflammatory

Catabolic metabolismTolerogenic

Anti-inflammatory

Warburg effect: Increaseanabolic pathwaysGeSIDA2019

Valle-Casuso et al. Cell Metab 2019

HIV INMUNOPATHOGENESIS AND INMUNOMETABOLISM

GeSIDA2019

Metabolic Profiles Coincide with CD4+ T Cell Subsets Susceptibility to HIV-1 Infection

Valle-Casuso et al. Cell Metab 2019

GeSIDA2019

Metabolic Profiles Coincide with CD4+ T Cell Subsets Susceptibility to HIV-1 Infection

Valle-Casuso et al. Cell Metab 2019

GeSIDA2019

Inhibition of Cell Metabolic Pathways Blocks HIV-1 Infection of CD4+ T Cells

Valle-Casuso et al. Cell Metab 2019

GeSIDA2019

Palmer et al. EBiomedicine 2016

INMUNOPATHOGENESIS AND INNATE INMUNOMETABOLISM : MONOCYTE/MACROPHAGE AND DCs

GeSIDA2019

pDCs: A LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY

NTLR9

BDCA-2INF-α

TLR7

CD40

CD86

MHC-2

CCR7

TRAIL

MHC-1

Stimulus

pDC

N

TLR9

BDCA-2

TLR7

< 1% PBMCs

N

DC

N

NK

N

CD4

N

CD8

TLR2

Mono

N

CD4

TLR4

Kadowaki et al. J Exp Med 2000

Fonteneau et al. Blood 2003

Kawamura et al. Blood 2006

O’Brien et al. J Clin Inv 2011

Machmach et al. J Virol 2012

GeSIDA2019

Dominguez-Molina et al. Front Immunol 2019

pDCs: A LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY

0 500 1000 1500 20000

1

2

3

r=-0.69p=0.007

pyruvic_acid%

pD

Cs

Tarancon-Diez et al. Unpublished observations

GeSIDA2019

PDCs GEN EXPRESSION PROFILE ASSOCIATED WITH PDCs METABOLIC PROFILE

pDC

NTLR9

N

TLR9

CONTROLADOR

VIH

pDC

NTLR9

N

TLR9

NO CONTROLADOR

VIH

50 genes

Tarancon-Diez et al. GESIDA 2017

Tarancon-Diez et al. Unpublished

GeSIDA2019

GLICOLISISOXPHOS

FENOTIPO CONTROLADOR

GLICOLISIS

OXPHOS

FENOTIPO PROGRESOR

CEACAM-1 PI3k/AKT pathway Apoptosis mediada mitocondria

p21 Síntesis de nucleótidos Inhibición síntesis Replicación viral

SLAMF1 Regulación NADPH Oxidasa ROS

NCF4 Subunidad NADPH Oxidasa ROS

PDCs GEN EXPRESSION PROFILE ASSOCIATED WITH PDCs METABOLIC PROFILE

GeSIDA2019

CpgA/16 hControl

CpgC/16 hControl

CpG

AAT-2

CpG

C

0

2

4

6

8

10HEX

HIF-1a

LDH

Fo

ld c

han

ge e

xp

ressio

n

(resp

ect

NS

co

nd

itio

n)

METABOLIC FLUX IN pDCs AFTER DIFFERENT TLR STIMULI

Gasca-Capote et al Unpublished observations

GeSIDA2019

PERSISTENT CONTROLLER PHENOTYPE: THE RIGHT MODEL OF FUNCTIONAL CURE

GeSIDA2019

THANKS!

EC-

LABORATORIO DE INFECCIÓN POR VIH Y FARMACOCINÉTICA DE ANTIVIRALES, IBIS/HOSPITAL U. VIRGEN DEL ROCÍOAll members, specially to:

Beatriz Dominguez-Molina Reyes Jimenez-LeónLaura Tarancón-Diez Carmen Gasca-Capote

All members, specially to:

FRANCISCO VIDAL/ESTHER RODRIGUEZ (H. JOAN XXIII, TARRAGONA)CECILIO LOPEZ-GALINDEZ/M. PERNAS/C. CASADO (ISCIII, MADRID)CARMEN RODRIGUEZ/JORGE DEL ROMERO (C. SANDOVAL, MADRID)AGATHE LEON/FELIPE GARCÍA (H. CLINIC, BARCELONA)JOSE MIGUEL BENITO/NORMA RALLÓN (I.I. F. JIMENEZ DIAZ, MADRID)

IMMUNOLOGY LABORATORY, VRC, NIAID, NIH, BETHESDA, MARYLAND, USA.RICHARD A. KOUP

SINGAPORE IMMUNOLOGY NETWORK, SINGAPORE.ANIS LARBI

HASSEN KAREDConsejería de Salud Junta de AndalucíaNicolás Monardes Program (C-0032/17)

GeSIDA2019

FENOTIPOPROGRESOR TÍPICO

FENOTIPOPROGRESOR RÁPIDO

FENOTIPOCONTROLADOR

FENOTIPO¿ERRADICADOR?

ESPECTRO DE FENOTIPOS DE PROGRESIÓN EN LA INFECCIÓN POR VIH

GeSIDA2019

Pernas, Tarancón et al. J Virol 2018

POTENCIALES “ERRADICADORES” DEL VIH

GeSIDA2019

Pernas, Tarancón et al. J Virol 2018

50%

NO VIRUS

POTENCIALES “ERRADICADORES” DEL VIH

GeSIDA2019

POTENCIALES “ERRADICADORES” DEL VIH

CP Erradicadores

0.0

0.2

0.4

0.6

0.80.01

Índice de polifuncionalidadCD8+ (IL2, TNFa, IFNg, CD107a, PRF)

pIN

DE

X

MFI b7_CD1c

CP Erradicadores0

200

400

600

800

MF

I b

7+

CD

1c+

GeSIDA2019

Alzahrani et al. EBiomedicine 2019

LINK BETWEEN DYSBIOSIS AND INMUNOMETABOLISM

GeSIDA2019

LINK BETWEEN INCREASED GLYCOLYSIS AND INFLAMMATION

Aounallah et al. Cytokine & Growth Factor Reviews 2016

GeSIDA2019