Download Diapositiva 1

ERAP2 (Endoplasmic Reticulum-Associated Aminopeptidase 2)
plays a role in resistance to HIV-1 infection
PhD student: Irma Saulle
[email protected]
Poster: MOPDA0102
University of Milan
N
C
ERAP2
ERAP2
Basic groove
ERAP2 trims peptides to optimal size
for loading onto MHC I molecules and
shapes the antigenic repertoire
presented to CD8+ T lymphocytes
Introduction
ERAP2 gene organization
Haplotype A
Haplotype B
ERAP2-FL
ERAP2-AS
ERAP2
960 aa
120KDa
gtAagga
ERAP2
534 aa
60KDa
gtGagga
Stop codons
AIMS
To confirm the correlation between ERAP2 haplotypes and susceptibility to HIV-1 infection
To understand the mechanism of action of the two haplotypes
2
Results
Association study for rs2549782 in HESN
Combineda
Association study in the Spanish IDU-HESN cohort
Phenotype
Genotype counts
(GG/GT/TT)
Genotype counts
(recessive model,
GG/GT+TT)
P
(recessive
model)
OR (95% CI)
Het. pvalueb
I2 c pmetad
ORmetae
IDU-HESN
27/46/31
27/77
0.0392
0.50( 0.26 -0.97)
0.42
0 9.6 x10-5 0.41
HC
19/75/36
19/111
homoA subjects are protected from HIV-1 infection
Co-segregation analysis of HLA-B*57 with rs2549782 genotypes in HESN and HIV+
Phenotype
HESN
HIV+
HLA-B*57 status
rs2549782 genotype
GG (homoA)
GT or TT (non-homoA)
HLA-B*57+
6
3
HLA-B*57-
13
46
HLA-B*57+
5
9
HLA-B*57-
29
144
p value
0.011
0.14
HESN phenotype is associated with the co-presence of the HLA-B*57 allele and the homoA
status at ERAP2
3
Results
mRNA basal expression for ERAP2-FL, ERAP2-AS
and ERAP2-TOT
AA
AA
AA
AB
AA
AB
AB
AA
AB
35 Homo-A (27%)
BB
AB
64 Hetero-AB (43%)
BB
BB
40 Homo-B (30%)
ERAP2-AS
ERAP2-FL
BB
BB
BB
ERAP2-TOT
P < 0.005
P < 0.005
P < 0.005
120
120
600
P < 0.005
80
400
60
300
60
200
40
20
100
20
0
HomoA HeteroAB HomoB
P < 0.005
80
40
0
P < 0.05
100
500
NFOLD
NFOLD
100
140
700
NFOLD
140
HomoA HeteroAB HomoB
0
HomoA HeteroAB HomoB
Subjects with different ERAP2 genotype express different amounts of ERAP2
4
Results
PBMC
P < 0.005
CD4+
p24 (pg/ml)
log 10
P < 0.005
Subjects with different ERAP2 genotype show a different susceptibility to HIV-1 infection
HLA- ABC
Mean fluorescence intensity
P < 0.005
P < 0.005
P < 0.005
P < 0.005
Uninfected
PBMC
HIV-infected
PBMC
The expression of genes involved in antigen processing and presentation, and MHC class I
molecules are increased in homoA subjects
5
Conclusion
ERAP2
mRNA levels
Subjects with different ERAP2 genotypes show
different expression of :
MHC class I
molecules
Antigen processing & presentation
pathway
Different alleles of ERAP2 are able to generate a diverse antigen
repertoire capable of activating different and likely more 6
6
protective lymphocyte clones.
Chair of Immunology
University of Milan
Prof. Mario Clerici
Prof. Daria Trabattoni
Dr. Mara Biasin
Dr. Mariacristina De Luca
Dr. Francesca La Rosa
Dr. Federica Gnudi
Dr. Veronica Rainone
Dr. Micaela Garziano
Dr. Salomè Ibba
Dr. Sara Yahyaei
Dr. Angela Berzi
PhD student: Irma Saulle
University of Milan
Email: [email protected]
Infectious Disease Unit
S.M. Annunziata Hospital, Firenze
Dr. Sergio Lo Caputo
Dr. Francesco Mazzotta
Scientific Institute for Recovery and
Care E. Medea
Dr. Manuela Sironi
Dr. Rachele Cagliani
Infectious Disease and Microbiology
Clinical Unit
Valme Hospital, Spain
Dr. Juan Macìas
Dr. Juan A. Pineda
Dr. Antonio Caruz
7