Abacavir Forms Novel Cross-Linking
Abacavir Protein Adducts in Patients
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Abstract
Abacavir
(ABC), a nucleoside-analogue reverse transcriptase inhibitor, is associated
with severe hypersensitivity reactions that are thought to involve
the activation of CD8+ T cells in a HLA-B*57:01-restricted manner.
Recent studies have claimed that noncovalent interactions of ABC with
HLA-B*57:01 are responsible for the immunological reactions associated
with ABC. However, the formation of hemoglobin-ABC aldehyde (ABCA)
adducts in patients exposed to ABC suggests that protein conjugation
might represent a pathway for antigen formation. To further characterize
protein conjugation reactions, we used mass spectrometric methods
to define ABCA modifications in patients receiving ABC therapy. ABCA
formed a novel intramolecular cross-linking adduct on human serum
albumin (HSA) in patients and <i>in vitro</i> via Michael
addition, followed by nucleophilic adduction of the aldehyde with
a neighboring protein nucleophile. Adducts were detected on Lys159,
Lys190, His146, and Cys34 residues in the subdomain IB of HSA. Only
a cysteine adduct and a putative cross-linking adduct were detected
on glutathione <i>S</i>-transferase Pi (GSTP). These findings
reveal that ABC forms novel types of antigens in all patients taking
the drug. It is therefore vital that the immunological consequences
of such pathways of haptenation are explored in the <i>in vitro</i> models that have been used by various groups to define new mechanisms
of drug hypersensitivity exemplified by ABC