ERAP2 (Endoplasmic Reticulum-Associated Aminopeptidase 2)

plays a role in resistance to HIV-1 infection

University of Milan

PhD student: Irma Saulleirma.saulle@unimi.itPoster: MOPDA0102

ERAP2

8-9 aa residuesN

C

Basic grooveERAP2

ERAP2 trims peptides to optimal size for loading onto MHC I molecules and

shapes the antigenic repertoire presented to CD8+ T lymphocytes

ERAP2 gene organization

Stop codons

ERAP2960 aa120KDa

ERAP2534 aa60KDa

ERAP2-AS

ERAP2-FL gtAagga

gtGagga

Haplotype A

Haplotype B

AIMSTo confirm the correlation between ERAP2 haplotypes and susceptibility to HIV-1 infection

To understand the mechanism of action of the two haplotypes

Introduction

2

Association study in the Spanish IDU-HESN cohort   Combineda

Phenotype Genotype counts(GG/GT/TT)

  Genotype counts (recessive model, GG/GT+TT)

P (recessive model)

OR (95% CI)   Het. p-valueb

I2 c pmetad ORmeta

e

IDU-HESN 27/46/31   27/77 0.0392 0.50( 0.26 -0.97)   0.42 0 9.6 x10-5 0.41HC 19/75/36   19/111              

Phenotype   HLA-B*57 status   rs2549782 genotype   p value

        GG (homoA) GT or TT (non-homoA)    

HESN   HLA-B*57+   6 3   0.011

    HLA-B*57-   13 46    

               

HIV+  HLA-B*57+   5 9   0.14

    HLA-B*57-   29 144    

               

Association study for rs2549782 in HESN

homoA subjects are protected from HIV-1 infection

HESN phenotype is associated with the co-presence of the HLA-B*57 allele and the homoA status at ERAP2

Co-segregation analysis of HLA-B*57 with rs2549782 genotypes in HESN and HIV+

Results

3

BBBBBB BB

BB

35 Homo-A (27%) 40 Homo-B (30%)64 Hetero-AB (43%)

AAAA

AA

AA

AA ABAB

AB

ABAB BB

ERAP2-FL

HomoA HeteroAB HomoB 0

20

40

60

80

100

120

140

P < 0.005

NFO

LD

P < 0.005

P < 0.005

NFO

LD

0

100

200

300

400

500

600

700

ERAP2-AS

HomoA HeteroAB HomoB

P < 0.005

ERAP2-TOT

0

20

40

60

80

100

120

140

HomoA HeteroAB HomoB

NFO

LD

P < 0.005

P < 0.05

mRNA basal expression for ERAP2-FL, ERAP2-AS and ERAP2-TOT

Subjects with different ERAP2 genotype express different amounts of ERAP2

Results

4

CD4+P < 0.005

P < 0.005

PBMC

p24

(pg/

ml)

log

10

HLA-

ABC

Mea

n flu

ores

cenc

e in

tens

ity

Uninfected PBMC

HIV-infected PBMC

P < 0.005

P < 0.005P < 0.005

P < 0.005

Subjects with different ERAP2 genotype show a different susceptibility to HIV-1 infection

The expression of genes involved in antigen processing and presentation, and MHC class I molecules are increased in homoA subjects

Results

5

6

Different alleles of ERAP2 are able to generate a diverse antigen repertoire capable of activating different and likely more

protective lymphocyte clones.

Subjects with different ERAP2 genotypes show different expression of :

ERAP2 mRNA levels

Antigen processing & presentation pathway

MHC class I molecules

Conclusion

6

PhD student: Irma Saulle University of MilanEmail: irma.saulle@unimi.it

Chair of ImmunologyUniversity of Milan

Prof. Mario ClericiProf. Daria TrabattoniDr. Mara BiasinDr. Mariacristina De LucaDr. Francesca La RosaDr. Federica GnudiDr. Veronica RainoneDr. Micaela GarzianoDr. Salomè IbbaDr. Sara YahyaeiDr. Angela Berzi

Infectious Disease Unit S.M. Annunziata Hospital, FirenzeDr. Sergio Lo CaputoDr. Francesco Mazzotta

Scientific Institute for Recovery and Care E. MedeaDr. Manuela SironiDr. Rachele Cagliani

Infectious Disease and Microbiology Clinical UnitValme Hospital, Spain Dr. Juan MacìasDr. Juan A. PinedaDr. Antonio Caruz

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