IFN-gamma exposes a cryptic cytotoxic T lymphocyte epitope in HIV-1 reverse transcriptase

The proteasome, an essential component of the ATP-dependent proteolytic pat hway in eukaryotic cells, is responsible for the degradation of most cellul ar proteins and is believed to be the main source of MHC class I-restricted antigenic peptides for presentation to CTL. Inhibition of the proteasome b y lactacystin or various peptide aldehydes can result in defective Ag prese ntation, and the pivotal role of the proteasome in Ag processing has become generally accepted. However, recent reports have challenged this observati on, Here we examine the processing requirements of two HLA A*0201-restricte d epitopes from HIV-1 reverse transcriptase and find that they are produced by different degradation pathways, Presentation of the C-terminal ILKEPVHG V epitope is impaired in ME275 melanoma cells by treatment with lactacystin , and is independent of expression of the IPN-gamma-inducible proteasome be ta subunits LMP2 and LMP7. In contrast, both lactacystin treatment and expr ession of LMP7 induce the presentation of the N-terminal VIYQYMDDL epitope, Consistent with these observations we show that up-regulation of LMP7 by I FN-gamma enhances preservation of the VIYQYMDDL epitope, Hence interplay be tween constitutive and IFN-gamma-inducible beta-subunits of the proteasome can qualitatively influence Ag presentation. These observations may have re levance to the patterns of immunodominance during the natural course of vir al infection.