Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection.

Human ERAP1 and ERAP2 encode two endoplasmic reticulum aminopeptidases. These enzymes trim peptides to optimal size for loading onto major histocompatibility complex class I molecules and shape the antigenic repertoire presented to CD8(+) T cells. Therefore, ERAP1 and ERAP2 may be considered potential selection targets and modulators of infection susceptibility. We resequenced two genic regions in ERAP1 and ERAP2 in three HapMap populations. In both cases, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and reduced population genetic differentiation. The genealogy of ERAP1 and ERAP2 haplotypes was split into two major branches with deep coalescence times. These features suggest that long-standing balancing selection has acted on these genes. Analysis of the Lys528Arg (rs30187 in ERAP1) and Asn392Lys (rs2549782 in ERAP2) variants in an Italian population of HIV-1-exposed seronegative (ESN) individuals and a larger number of Italian controls indicated that rs2549782 significantly deviates from Hardy-Weinberg equilibrium (HWE) in ESN but not in controls. Technical errors were excluded and a goodness-of-fit test indicated that a recessive model with only genetic effects adequately explains HWE deviation. The genotype distribution of rs2549782 is significantly different in the two cohorts (P = 0.004), mainly as the result of an over-representation of Lys/Lys genotypes in the ESN sample (P-value for a recessive model: 0.00097). Our data suggest that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 confer resistance to HIV-1 infection possibly via the presentation of a distinctive peptide repertoire to CD8(+) T cells.