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Endoplasmic reticulum aminopeptidase 2 haplotypes play a role in modulating susceptibility to HIV infection

Biasin, Maraa,*; Sironi, Manuelab,*; Saulle, Irmaa; de Luca, Mariacristinaa; la Rosa, Francescaa; Cagliani, Racheleb; Forni, Diegob; Agliardi, Cristinag; Caputo, Sergio loc; Mazzotta, Francescoc; Trabattoni, Dariaa; Macias, Juand; Pineda, Juan A.d; Caruz, Antonioe; Clerici, Mariof,g

doi: 10.1097/QAD.0b013e3283601cee
Basic Science

Objective: Haplotype-specific alternative splicing of the endoplasmic reticulum (ER) aminopeptidase type 2 (ERAP2) gene results in either full-length (FL, haplotype A) or alternatively spliced (AS, haplotype B) mRNA. As ERAP2 trims peptides loaded on major histocompatibility complex (MHC) class I and CD8+ T lymphocytes protect against viral infections, we analysed its role in resistance to HIV-1 infection.

Methods: ERAP2 polymorphisms were genotyped using a TaqMan probe, and human leukocyte antigen (HLA) typing of class-I HLAB locus was performed by single specific primers-polymerase chain reaction method. To verify whether ERAP2 genotype influences susceptibility to HIV-1 infection in vitro we performed HIV-1 infection assay. We evaluated antigen presentation pathway with PCR array and the viral antigen p24 with ELISA.

Results: Genotype analysis in 104 HIV-1-exposed seronegative individuals (HESNs) exposed to HIV through IDU-HESN and 130 controls from Spain indicated that hapA protects from HIV infection. Meta-analysis with an Italian cohort of sexually exposed HESN yielded a P value of 7.6 × 10–5. HLAB typing indicated that the HLA-B*57 allele is significantly more common than expected among HESN homozygous for haplotype A (homoA). Data obtained in a cohort of 139 healthy Italian controls showed that following in-vitro HIV-1 infection the expression of ERAP2-FL and a number of genes involved in antigen presentation as well as of MHC class I on the surface of CD45+ cells was significantly increased in homoA cells; notably, homoA peripheral blood mononuclear cells, but not isolated CD4+ cells, were less susceptible to HIV-1 infection.

Conclusion: ERAP2 hapA is correlated with resistance to HIV-1 infection, possibly secondarily to its effect on antigen processing and presentation.

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aDepartment of Biomedical and Clinical Sciences, University of Milan Milan

bScientific Institute IRCCS E.MEDEA, Bosisio Parini

cS. Maria Annunziata Hospital, Florence, Italy

dInfectious Diseases and Microbiology Clinical Unit, Valme Hospital, Seville

eImmunogenetics Unit, University of Jaen, Campus Las Lagunillas SN, Jaen, Spain

fDepartment of Physiopathology Medical-Surgery and Transplantation, University of Milan, Milan

gDon C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.

*M.B. and M.S. contributed equally to the writing of this article.

Correspondence to Mara Biasin, PhD, Chair of Immunology, Department of Biomedical and Clinical Sciences, University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy. Tel: +39 025 031 9681; fax: +39 02 5031 9677; e-mail:

Received 23 November, 2012

Revised 15 January, 2013

Accepted 11 February, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.