AN ALTERNATIVE TRANSLATIONAL READING FRAME ENCODES AN IMMUNODOMINANT RETROVIRAL CTL DETERMINANT EXPRESSED BY AN IMMUNODEFICIENCY-CAUSING RETROVIRUS

Recognition of virus-infected or transformed cells by CD8(+) CTL requi res a trimolecular complex composed of MHC class I, beta(2)-microglobu lin, and a specific foreign peptide composed of 8 to 10 linear amino a cids. The generation of such CTL epitopes has traditionally been thoug ht to be from the primary open reading frame encoding the viral or tum or-associated proteins. In this report it is demonstrated that a viral CTL epitope can also be generated from an alternative reading frame. Using a combination of synthetic peptides and Sindbis or vaccinia expr ession systems, MHC class I Kd-restricted BALB/cByJ CTL directed again st defective gag gene constructs of the LP-BM5 virus complex that caus es murine AIDS were shown to have specificity for the antigenic peptid e SYNTGRFPPL. This epitope is generated in a novel fashion from the se cond open reading frame (ORF2) of both the defective and ecotropic hel per virus components of LP-BM5. Importantly, lysis of target cells exp ressing BM5 ecotropic helper, and/or defective viral gag, demonstrated that the SYNTGRFPPL epitope is generated during the course of a norma l retroviral infection. Furthermore, MAIDS-resistant BALB/cByJ mice al so generated secondary restimulated CTL specific for SYNTGRFPPL follow ing in vivo priming with the LP-BM5 retroviral complex. These data sug gest that retroviruses, and potentially other viruses and foreign gene s, are capable of expressing T cell epitopes from alternative open rea ding frames. If one considers the influence of self peptides on T cell development, these ''alternative reading frame-derived'' peptides cou ld provide an important additional influence on the functional T cell repertoire.