HLA-E*01:01 allele is associated with better response to anti-HCV therapy while homozygous status for HLA-E*01:03 allele increases the resistance to anti-HCV treatments in frequently transfused thalassemia patients

Background: HLA-E binding to NKG2A/CD94 induces inhibitory signals that modulate NK cells cytotoxicity against infected targets. HCV-derived peptides stabilize HLA-E molecule that favours its higher expression. However, HLA-E stability and expression vary in different genotypes where the presence of HLA-E*01:03 allele is associated with higher HLA-E expression on targets that enhances NK cells inhibition and increases the chance of virus to escape from innate immune system. Here, we aimed to investigate whether HLA-E polymorphism affects HCV infection status or its treatment in major thalassemia patients who are more vulnerable to hepatitis C. Methods and materials: Study included 89 cases of major thalassemia positive for HCV-antibody; of those 17 patients were negative for HCV-PCR (spontaneously cleared) and 72 patients were HCV-PCR positive (persistent hepatitis under different anti-viral treatment). 16 major thalassemia patients without hepatitis, negative for HCV-antibody were also considered as patients control group. Genomic DNAs extracted from whole bloods were genotyped for HLA-E locus using a sequence specific primer-PCR strategy. Results: In thalassemia patients, HLA-E*01:03 allele increased susceptibility to HCV infection [p = 0.02; 4.74(1.418-15.85)]. In addition, HLA-E*01:03/*01:03 genotype predicted more resistance to HCV treatment compared to other genotypes [p = 0.037; 3.5(1.1-11.4)]. In other words, we found that the presence of HLA-E*01:01 allele favors better response to anti-HCV therapy [p = 0.037; 3.5(1.1-11.4)]. Conclusion: From a mechanistic point of view, the associations between HLA-E polymorphisms and susceptibility to HCV infection or its therapeutic resistance in thalassemia patients may suggest potential roles for the innate and adaptive immune responses to this infection, which are manifested by the acts of HLA-E - NKG2A/CD94 axis in the modulation of NK cell inhibitory function as well as HLA-E associated CD8' T cell cytolytic activity against HCV, respectively. Notably, from a clinical point of view, paying attention to these associations may not only be useful in increasing the effectiveness of current antiHCV regimens comprising direct acting antivirals (DAAs) in more complicated patients, but may also suggest antiviral prophylaxis for patients more vulnerable to HCV infection. (c) 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Automated summary

HLA-E polymorphism affects HCV infection and treatment in major thalassemia patients. The HLA-E*01:03 allele increases susceptibility to HCV infection, while the HLA-E*01:03/*01:03 genotype is associated with higher resistance to HCV treatment.