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

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

doi:10.1371/journal.ppat.1013497

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

Journal article

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

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

PLoS pathogens, Vol.21(9), e1013497

2025

DOI: https://doi.org/10.1371/journal.ppat.1013497

PMID: 40972103

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Abstract

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.

Details

Title: The association of class II HLA alleles with tuberculosis-associated immune reconstitution inflammatory syndrome
Authors/Creators: Phuti Choshi - University of Cape Town
Sarah Pedretti - University of Cape Town
Tafadzwa Chimbetete - University of Cape Town
Rama Gangula - Vanderbilt University Medical Center
Muki Shey - Wellcome Centre for Infectious Diseases Research in Africa
Cari Stek - Wellcome Centre for Infectious Diseases Research in Africa
Rachel P J Lai - Imperial College London
Robert Wilkinson - The Francis Crick Institute
Graeme Meintjes - Queen Mary University of London
Elizabeth Phillips - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
Jonny Peter - University of Cape Town
Publication Details: PLoS pathogens, Vol.21(9), e1013497
Publisher: Public Library of Science
Number of pages: 8
Identifiers: 991005815049107891
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.194 Tuberculosis & Leprosy; 1.194.273 TB Diagnostics & Treatment
Web Of Science research areas: Microbiology; Parasitology; Virology
ESI research areas: Microbiology