Pharmacology: A false sense of non-self

Abstract

Elucidation of abacavir hypersensitivity syndrome in HIV-1 patients establishes a new pharmacogenetic paradigm. A drug can alter the bodies’ surface display of peptides bound to a given HLA molecule, thereby initiating life threatening T-cell reactions against self-peptides not previously exposed to the immune system.

Figure 1. A case of mistaken identity

a) CD8 CTL kill virally infected cells whose surface HLA molecules display peptides derived from viral proteins. In the cytoplasm, both foreign viral proteins (red) and endogenous self-proteins (blue) are cleaved by the proteosome into multiple peptides (represented by different shapes). Then a subset is transported via TAP into the endoplasmic reticulum. Those peptides matching a specific HLA molecule’s binding motif are loaded for export and cell surface display. Viral peptides associated with self-HLA are recognized as foreign, engendering a brisk CTL response to destroy the infected cell. In contrast, CTL do not kill uninfected cells, since self-peptide reactive T cells were deleted by thymic tolerance mechanisms early in life. b) Administration of a specific HLA-binding drug, like abacavir, alters the HLA peptide binding characteristics of the allele with which it interacts (HLA-B*57:01), thereby loading and displaying “new” self-peptides on the antigen-presenting cell surface. Since this “new” self-peptide (3-lobe clover symbol) was not displayed during thymic tolerance induction, “new” self-peptide specific CTL (blue) were not deleted and, hence, unleash an immune attack causing AHS. In panels A and B, only an individual viral or self-peptide and one corresponding CD8 CTL is shown for simplicity.