Journal Article

The association of class II HLA alleles with tuberculosis-associated immune reconstitution inflammatory syndrome

Shey, Muki, Phillips, Elizabeth, Chimbetete, Tafadzwa, Gangula, Rama, Wilkinson, Robert, Pedretti, Sarah, Meintjes, Graeme, Lai, Rachel P. J., Stek, Cari, Peter, Jonny, Choshi, Phuti

2025

Overview

Genetic associations within the human leukocyte antigen (HLA) gene complex and linked genes in TB-IRIS outcomes remains population specific and not well understood. Here, we conducted a study including well characterised HIV-TB coinfected patients with (n = 86) and without (n = 124) TB-IRIS from the randomized, double-blind, prophylactic prednisone trial (PredART study) with HLA, ERAP and KIR genotyping data. We confirmed the association of TB-IRIS with lower CD4 counts pre-ART initiation. We identified nine classical class I and II HLA alleles protective against TB-IRIS, while four alleles were linked to increased risk. Associations ranged from strongly protective (HLA-DQB1*05:01, OR: 0.07, 95%CI: 0.02-0.28, Pc < 0.001) to strongly risk associated (notably DRB1*01:02, OR: 5.92, 95%CI: 1.36-26.7, Pc = 0.028), with conflicting signals at the HLA-DRB1 locus. Conditional regression analysis revealed that residue E71 at the polymorphic position 71 within the HLA-DRB1 peptide-binding groove was critical, and grouping of HLA-DRB1 alleles by the residue at position 71 corresponded with differential TB-IRIS association. In conclusion, this study identifies population-specific genetic factors influencing TB-IRIS susceptibility and highlights a potential mechanistic role for specific HLA-DRB1 residues in modulating immune responses during ART.

• Publisher: Public Library of Science,PLOS,Public Library of Science (PLoS)
• Subject: Adult / Alleles / Allelomorphism / Amino acids / Analysis / Antigens / Antiretroviral therapy / Biology and Life Sciences / Care and treatment / CD4 antigen / Coinfection / Corticosteroids / Cytokines / Cytomegalovirus / Diagnosis / Disease susceptibility / Double-Blind Method / Drb1 protein / Female / Genes / Genetic aspects / Genetic factors / Genetic Predisposition to Disease / Genetic variation / Genotyping / Grooves / Histocompatibility antigen HLA / Histocompatibility antigens / Histocompatibility Antigens Class II - genetics / HIV / HIV (Viruses) / HIV Infections - complications / HIV Infections - drug therapy / HIV Infections - genetics / HIV Infections - immunology / HLA histocompatibility antigens / HLA-DRB1 Chains - genetics / Human immunodeficiency virus / Humans / Immune reconstitution / Immune Reconstitution Inflammatory Syndrome - genetics / Immune Reconstitution Inflammatory Syndrome - immunology / Immune Reconstitution Inflammatory Syndrome - prevention & control / Immune response / Leukocytes / Male / Medicine and Health Sciences / Middle Aged / Peptides / Physical Sciences / Population genetics / Population studies / Prednisone / Regression analysis / Research and Analysis Methods / Residues / Risk factors / Short Reports / Testing / Tuberculosis / Tuberculosis - complications / Tuberculosis - drug therapy / Tuberculosis - genetics / Tuberculosis - immunology