Role of HLA-B α-3 domain amino acid position 194 in HIV disease progression

Abstract

HLA class I molecules play a role in the regulation of innate immune response. Therefore, the interaction of HLA class I molecules with different activating and inhibitory receptors leads to balancing the immune response. Among the different family of receptors, NK receptors KIR3DL1/S1 and LIR1, play a major role. Aim of this study was to evaluate the role of amino acid polymorphic positions of HLA class I molecules interacting with NK receptors in HIV progression. In order to minimize the influence of viral variability, a cohort of children with a nosocomial monophyletic HIV-1 infection from the Benghazi Children Hospital has been evaluated. To assess the role of single amino acid positions, we translated all HLA alleles in the different amino acid position polymorphisms. Interestingly, the polymorphism Val 194 located in the α3-domain of HLA-B, resulted associated with LTNP (LTNP=73.08%, FP=34.78%; P<0.02). When Val is present at position 194, HLA-B is known to interact with the receptor LIR1 (ILT2/LILRB1/CD85j). Therefore, we analyzed the role of the polymorphism in position 194 in HLA-B/LIR1 interaction by homology molecular modeling. The change Val to Ile at position 194 alters significantly the network of interaction between the amino acid residues of HLA-B and LIR1. In conclusion, considering the limitation of the small population evaluated, polymorphisms outside the peptide binding region of the HLA class I molecule can play a key role in HIV progression through interaction with other immune-relevant receptors.