ENDOPLASMIC RETICULUM AMINOPEPTIDASE 2 HAPLOTYPES PLAY A ROLE IN MODULATING SUSCEPTIBILITY TO HIV-1 INFECTION

Background: The endoplasmic reticulum aminopeptidase type 2 (ERAP2) undergoes haplotype-specific alternative splicing which results in the production of either full-length (FL, from haplotype A ) or alternatively spliced (AS, from haplotype B) mRNA Resistance to HIV infection in a cohort of Italian sexually HIV-exposed seronegative individuals (HESN) is recently associated with a variant in ERAP2 that tags haplotype A. As the protein product of this gene trims peptides loaded on MHC class I, shaping the quality of viral peptides that are presented to CD8+T cells, we further analysed its role in HIV-1-susceptibility. Methodology: ERAP2 was genotyped in a cohort of 104 Spanish HESN individuals exposed to HIV through injection drug use (IDU-HESN). In parallel PBMCs isolated from 139 healthy controls (HC) grouped according to their ERAP2 genotype were infected with HIV-1 and analysed for: 1)expression levels of mRNA specific for ERAP2 and for 84 genes involved in the antigen presentation pathway; 2) MHC class I MFI on CD45 Ba-L cells; 3)susceptibility to HIV-1 infection; 4) ERAP2 protein expression. Finally, we analyzed the co-segregation of HLA-B*57 with ERAP2 haplotype in a previously described cohort of Italian sexually-exposed HESN. Results: Genotype analysis in IDU-HESN mirrored the previous association between ERAP2 haplotype A and protection from HIV infection; meta-analysis with the Italian cohort yielded a p value of 7.6 x10 Cosegregation analysis indicated that the HLA-B*57 allele is significantly more common among HESN homozygous for haplotype A(homo A) compared to non-homo A (p=0.01), suggesting genetic interaction. Data obtained in HC showed that following in vitro HIV infection the expression of mRNA for ERAP2-FL and a number of genes involved in antigen processing and presentation as well as of MHC class I on the surface of CD45+ cells are significantly increased in homo A cells; notably, homoA peripheral blood mononuclear cells, but not isolated CD4 cells, were less susceptible to HIV-1 infection. Only the expression of ERAP2-FL could be detected by western blot analyses. Conclusions: haplotype A of ERAP2 confers resistance to HIV infection independently of the route of exposure; such variation possibly affects MHC presentation and immune response.