New genetic predictors for abacavir tolerance in HLA-B57:01 positive individuals

• Published in: Human immunology Vol. 81; no. 6; pp. 300 - 304
• Main Authors: Pavlos, Rebecca, Deshpande, Pooja, Chopra, Abha, Leary, Shay, Strautins, Kaija, Nolan, David, Thorborn, Daren, Shaefer, Mark, Rauch, Andri, Dunn, David, Montaner, Julio, Rachlis, Anita, Almeida, Coral-Ann, Choo, Linda, James, Ian, Redwood, Alec J., Li, Yueran, Gaudieri, Silvana, Mallal, Simon A., Phillips, Elizabeth J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2020
• Subjects: Abacavir hypersensitivity syndrome; Allergens - immunology; Aminopeptidases - genetics; Anti-HIV Agents - immunology; Anti-HIV Agents - therapeutic use; Dideoxynucleosides - adverse effects; Dideoxynucleosides - immunology; Dideoxynucleosides - therapeutic use; Drug Hypersensitivity Syndrome - etiology; Drug Hypersensitivity Syndrome - genetics; Drug-Related Side Effects and Adverse Reactions - genetics; Endoplasmic reticulum aminopeptidase 1; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HIV Infections - complications; HIV Infections - drug therapy; HIV-1 - physiology; HLA-B Antigens - genetics; Human leukocyte antigen; Humans; Lipopolysaccharide Receptors - genetics; Male; Minor Histocompatibility Antigens - genetics; Phenotype; Retrospective Studies; aa; IM-ADR; PREDICT-1; sCD14; PT; ADH; ERAP1; MHC; Endoplasmic reticulum aminopeptidase 1; Abacavir hypersensitivity syndrome; MAF; KIR; NPV; Human leukocyte antigen; PPV; LD; SNPs; CD14; ERAP; HLA; NK; ABC HSS
• ISSN: 0198-8859; 1879-1166; 1879-1166
• DOI: 10.1016/j.humimm.2020.02.011

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.