Differential Frequencies of HLA-DRB1, DQA1, and DQB1 Alleles and Haplotypes Are Observed in the Arbovirus-Related Neurological Syndromes

• Published in: The Journal of infectious diseases 2021-08, Vol.224 (3), p.517-525
• Main Authors: Sonon, Paulin, Brito Ferreira, Maria Lúcia, Santos Almeida, Renata, Saloum Deghaide, Neifi Hassan, Henrique Willcox, Glauco, Guimarães, Elizabeth Lima, da Purificação Júnior, Antônio Fernando, Cordeiro, Marli Tenório, Antunes de Brito, Carlos Alexandre, de Albuquerque, Maria de Fátima Militão, Lins, Roberto D, Donadi, Eduardo A, Lucena-Silva, Norma
• Format: Article
• Language: English
• Subjects: Alleles; Arboviruses - genetics; Bone marrow; Bone marrow transplantation; Chikungunya virus; Dengue fever; DQA1 protein; Drb1 protein; Encephalitis; Gene Frequency; Genetic Predisposition to Disease; Genotypes; Haplotypes; Histocompatibility antigen HLA; HLA-DQ alpha-Chains; HLA-DQ beta-Chains - genetics; HLA-DRB1 Chains - genetics; Humans; Neurological complications; Neurological diseases; Oligonucleotides; Peptides; Syndrome; Zika Virus; Zika Virus Infection
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiaa764

Abstract Background We took advantage of the 2015–2016 Brazilian arbovirus outbreak (Zika [ZIKV]/dengue/chikungunya viruses) associated with neurological complications to type HLA-DRB1/DQA1/DQB1 variants in patients exhibiting neurological complications and in bone marrow donors from the same endemic geographical region. Methods DRB1/DQA1/DQB1 loci were typed using sequence-specific oligonucleotides. In silico studies were performed using X-ray resolved dimer constructions. Results The DQA1*01, DQA1*05, DQB1*02, or DQB1*06 genotypes/haplotypes and DQA1/DQB1 haplotypes that encode the putative DQA1/DQB1 dimers were overrepresented in the whole group of patients and in patients exhibiting peripheral neurological spectrum disorders (PSD) or encephalitis spectrum disorders (ESD). The DRB1*04, DRB1*13, and DQA1*03 allele groups protected against arbovirus neurological manifestation, being underrepresented in whole group of patients and ESD and PSD groups. Genetic and in silico studies revealed that DQA1/DQB1 dimers (1) were primarily associated with susceptibility to arbovirus infections; (2) can bind to a broad range of ZIKV peptides (235 of 1878 peptides, primarily prM and NS2A); and (3) exhibited hydrophilic and highly positively charged grooves when compared to the DRA1/DRB1 cleft. The protective dimer (DRA1/DRB1*04) bound a limited number of ZIKV peptides (40 of 1878 peptides, primarily prM). Conclusion Protective haplotypes may recognize arbovirus peptides more specifically than susceptible haplotypes. The 2015–2016 Brazilian arbovirus (ZIKV/DENV/CHIKV) outbreak caused severe neurological complications. We identified differential frequencies of HLA-DR/DQ variants associated with these complications. In silico studies revealed that protective dimers (DRA1/DRB1*04:01) recognize arbovirus peptides more precisely and efficiently than susceptibility dimers (DQA1*05/DQB1*02).