Presentación de PowerPoint · Ezequiel Ruiz-Mateos Carmona U.G. Clínica Enfermedades Infecciosas,...
Transcript of Presentación de PowerPoint · Ezequiel Ruiz-Mateos Carmona U.G. Clínica Enfermedades Infecciosas,...
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
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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%)
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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
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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%)
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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
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750
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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
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750
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250
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50
100
5 10 15 20
cART
Lo
g H
IV-1
co
p/m
L
GeSIDA2019
V
iro
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Im
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C
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0
2 0
4 0
6 0
8 0
1 0 0
%
HI
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co
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ll
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V
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a
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Im
m
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C
lin
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a
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s
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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
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
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
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