Proteomic Profiling and T Cell Receptor Usage of Abacavir Susceptible Subjects

Type B adverse drug reactions (ADRs) represent a significant threat as their occurrence arises unpredictable and despite proper application of the drug. The severe immune reaction Abacavir Hypersensitivity Syndrome (AHS) that arises in HIV+ patients treated with the antiretroviral drug Abacavir (ABC) strongly correlates to the presence of the human leukocyte antigen (HLA) genotype HLA-B*57:01 and discriminates HLA-B*57:01(+) HIV+ patients from ABC treatment. However, not all HLA-B*57:01(+) HIV+ patients are affected by AHS, implying the involvement of further patient-specific factors in the development of AHS. The establishment of a reliable assay to classify HLA-B*57:01 carriers as ABC sensitive or ABC tolerant allowed to investigate the T cell receptor (TCR) V beta chain repertoire of effector cells and revealed V beta 6 and V beta 24 as potential public TCRs in ABC sensitive HLA-B*57:01 carriers. Furthermore, distinct effects of ABC on the cellular proteome of ABC sensitive and tolerant volunteers were observed and suggest enhanced activation and maturation of dentritic cells (DC) in ABC sensitive volunteers. Analysis of ABC-naive cellular proteomes identified the T cell immune regulator 1 (TCIRG1) as a potential prognostic biomarker for ABC susceptibility and the involvement of significantly upregulated proteins, particularly in peptide processing, antigen presentation, interferon (IFN), and cytokine regulation.

Automated summary

Type B adverse drug reactions pose a significant threat to patients due to their unpredictable occurrence. In the treatment of HIV-positive patients, a severe immune reaction known as Abacavir Hypersensitivity Syndrome (AHS) can arise, which is strongly correlated to a specific gene. However, not all patients carrying this gene are affected by the reaction, suggesting the involvement of other factors. By classifying patients based on their gene profile and analyzing the cellular proteome, potential biomarkers for predicting drug susceptibility have been identified.