Gema Nieto, Manuel Sánchez, Ana Velasco i Joan Fibla
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Transcript of Gema Nieto, Manuel Sánchez, Ana Velasco i Joan Fibla
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Gema Nieto, Manuel Sánchez, Ana Velasco i Joan FiblaDepartament de Ciències Mèdiques Bàsiques-IRB LleidaUniversitat de Lleida
Variabilidad de genes del metabolismo de la vitamina D asociada con la infección por VIH y progresión a sida
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Acción pleiotrópica de la vitamina D
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Vitamin D biosynthesis
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The genomic actions of vitamin D are mediated by VDR
VDRE
Activation of Vitamin D responsive genes
transportsynthesis
Receptor binding
x
Repression of Vitamin D responsive genes
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VD y sistema immune
Modulación del balance Th1/Th2 Desplazamiento Th2
Respuesta innata Inhibición síntesis defensinas Inhibición maduración macrofagos y DCs
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Autoimmunty
Vitamin D ReceptorVitamin D Receptorvariability and diseasevariability and disease
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Autoimmunty
1-1--Hydroxilase (-Hydroxilase (CYP27B1CYP27B1))variability and diseasevariability and disease
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VDR Gene structure and disease associated variants
A1012G Poly A
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VDR variants: Genotype vs. Phenotype Causative variants?
Cdx: G allele diminished Cdx2 transcription factor binding
A1012G: lost of GATA binding site Fok I: 424 aa VDR (F allele) interacts more
efficiently with transcription factor TFIIB Functional interaction between polymorphisms
Marker variants? Bsm I & Poly A: mRNA stability is larger in Bsm I
“B” allele than in BsmI “b” allele? Haplotype BS vs. haplotype bL
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Arquitectura de transmisión región VDR
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CYP27B1 genetic variants
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Arquitectura de transmisión región CYP27B1
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HIV-1 primary infection and disease progression to AIDS
vs.VDR
CYP27B1
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Vitamina D & infecció VIH Vitamina D i sistema immune:
Resposta innata i vitamina D Maduració cèl.lules dendrítiques (DC) Balanç Th1 Th2- (desplaçament Th2) Síntesis local de vitamina D per macròfags i DC
Virus VIH Inducció de resposta Th1 Inducció mantinguda de resposta immune
VD i replicació viral Activació LTR viral per VD
VD i SIDA Disfuncions metabolisme VD durant la infecció Interaccions tractament i metabolisme VD
Variants VDR i infeccions Tuberculosis Lepra
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Variabilitat en la susceptibilitat a la
infecció
Variabilitat en la progressió clínica
Individus exposats no infectats
Ritme de progressió:•Progressors ràpids• Progressors lents• No progressors
Variabilitat fenotípica en la infecció per VIH-1
Quin paper juga el fons genètic de l'hoste en aquesta variabilitat?
Infeccions oportunistes
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VDR polymorphisms & HIV-1 primary infection
Cohorts considered At-risk HIV-1 uninfected subjets
Males IDU subjects Risk behaviour Markers of exposure (CCR5, Hepatitis C)
HIV-1 infected cohort Males IDU subjects
Healthy control subjects
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Patró de blocs en les cohorts analitzades
At-risk HIV-1 uninfected
Healthy controls HIV-1 infected
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VDR risk genotypes for HIV-1 infection
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Combined risk genotypes & HIV-1 infection
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Concluding remarks
VDR genotypes are associated with HIV-1 primary infection
VDR haplotypes and diplotypes associated with: Protection Risk
What about disease progression…?
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AIDS disease progression in HIV seropositive patients
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Disease progression: VDR & CYP27B1
SERLAC cohort 179 HIV-infected patients HIV positive test prior 1987
Disease Progression: Drop T-CD4 cell counts under 200/L AIDS progression according to:
CDC 1993 Incorporates AIDS-related diseases and CD4
cell counts under 200
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VDR and CYP27B1 variants tested
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Genotype association with AIDS CDC 1993 outcome
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Disease progression rates vs. VDR (rs1544410)
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Disease progression rates vs. CYP27B1 (rs464653)
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Disease progression rates vs. VDR-CYP27B1
(NRG)
(LRG)
(HRG)
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Combined genotype association with AIDS CDC 1993 outcome
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VDR diplotype status distribution
Haplotypes
Haplotype carriersAIDS cases/
AIDS free OR 95%CI P value
- - - A S 0 copies 34.9/36.6 11 copy 41.1/41.4 1 0.56-2 0,863
2 copies 20/5 4,2 1.4-4.5 0,006
G - - - S 0 copies 42.3/47.3 11 copy 38.3/32.7 1,3 0.7-2.4 0,426
2 copies 15.4/3.0 5,6 1.5-20.7 0,005
G - - A S 0 copies 46.4/49.8 11 copy 39.6/32.2 1,3 0.7-2.4 0,426
2 copies 10/1 10,9 1.3-88 0,007
- - - G L 0 copies 31,3/11,3 11 copy 37,6/44,6 0,3 1.16-0.67 0,003
2 copies 27/27 0,35 0.15-0.85 0,018
VDR , vitamin D receptor; AIDS, acquired immunodeficiency syndrome; OR, odds ratio; 95%CI, 95% confidence interval. Grey background indicates rare allele.
Table 43.- Distribution of carriers of selected VDR haplotypes according to AIDS 1993 status
rs1
787
8969
_L /
S
rs1
544
410_
G/A
rs1
073
5810
_C/T
rs4
516
035_
A/G
rs1
156
8820
_G/C
Haplotype copies
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Haplotips VDR i progressió
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Functional effects of associated genotypes
Testing immune related differences among VDR variants Th1 / Th2 response
In HIV patients and control subjects Levels of correceptor expression
In HIV patients T lymphocytes
In control subjects Macrophages T lymphocytes Dendritic cells
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UPPER_200
0
10
20
30
40
50
60
BSM_A/A
BSM_G/G
BSM_A/A 16,40625 3,595 25,64875 3,08875 3,28125 51,43375 8,4775 3,95875
BSM_G/G 20,84 3,644 25,108 5,594 3,584 38,592 6,86 4,302
PCT_CCR5 MINX_CCR5 PCT_CD4 PCT_CD4_CCR5 MINX_CD4_CCR5 PCT_CD8 PCT_CD8_CCR5 MINX_CD8_CCR5
LOWER_200
0
10
20
30
40
50
60
BSM_A/A
BSM_G/G
BSM_A/A 13,58 4,582 18,378 0,892 4,41 45,458 6,87 4,782
BSM_G/G 14,68 3,96 21,92 3,39 3,72 45,09 5,74 4,71
PCT_CCR5 MINX_CCR5 PCT_CD4 PCT_CD4_CCR5 MINX_CD4_CCR5 PCT_CD8 PCT_CD8_CCR5 MINX_CD8_CCR5
TOTAL
0,00
10,00
20,00
30,00
40,00
50,00
60,00
BSM_A/A
BSM_G/G
BSM_A/A 15,32 3,97 22,85 2,24 3,72 49,14 7,86 4,28
BSM_G/G 17,48 3,82 23,37 4,39 3,66 42,14 6,25 4,53
PCT_CCR5 MINX_CCR5 PCT_CD4 PCT_CD4_CCR5 MINX_CD4_CCR5 PCT_CD8 PCT_CD8_CCR5 MINX_CD8_CCR5
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
5
BSM_A/A
BSM_G/G
BSM_A/A 0,892
BSM_G/G 3,39
PCT_CD4_CCR5
P=0.077
P=0.028
Fondo Bsm_A/A Polarización Th2 CCR5 CCR5 libre ?? Fondo Bsm_G/G Polarización Th2 CCR5 CCR5 libre ??
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DC maturation & VD
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Expresión CD14
0
200
400
600
800
1000
1200
1400
0 M 10-9M 10-8M 10-7M
DOSIS VD
% F
LU
OR
ES
CE
NC
IA M
ED
IA
CO
NT
RO
L
bbBBG/G
A/A
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Expresión DC-SIGN
2030405060708090
100110
C- 10-9M 10-8M 10-7M
DOSIS VD
% F
LU
OR
ES
CE
NC
IA M
ED
IA
CO
NT
RO
L
bb
BBG/G
A/A
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La inhibición por VD de la maduración de DC es dependiente del genotipo VDR
La capacidad para montar una respuesta Th1 adecuada estará comprometida en un fondo
Bsm_A/A
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Corolario
Hipótesis La acción inmunomoduladora mediada
por vitamina D seria desfavorable en el contexto de la infección por VIH
Los genotipos asociados con infección y progresión corresponden a aquellos que median con una mayor eficiencia dicha acción
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Colaboracions establertes
Teresa Puig, Unitat VIH-sida Hospital Universitari Arnau de Bilanova, Lleida
Montse Planas, Hospital Clínic de Barcelona Benito Regueiro, Hospital Universitario de
Santiago de Compostela Antonio Caruz, Facultad de Ciencias
Universidad de Jaén Juan Antonio Pineda. Hospital Valme de
Sevilla Red de Investigación en SIDA (RIS)
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L’equip D…
Unitat de Genètica HumanaDep. de Ciencies Mèdiques BàsiquesIRB-LleidaUniversitat de Lleida
Manuel Sánchez
Ana Velasco
Gema Nieto
Yolanda Barber
Lídia Piedrafita
David Argiles
Joan Fibla