THE ROLE OF PROXIMAL AND DISTAL SEQUENCE VARIATIONS IN THE PRESENTATION OF AN IMMUNODOMINANT CTL EPITOPE ENCODED BY THE ECOTROPIC AK7 MULV

An emv-14-derived, replication-competent ecotropic murine leukemia vir us [MuLV], designated AK7, was previously cloned from the AKXL-5 recom binant inbred mouse strain and partially characterized. While genetica lly encoding for an envelope-derived immunodominant CTL epitope [KSPWF TTL] located in the transmembrane region of p15TM, this virus, unlike the emv-11-derived virus AKR623, fails to be efficiently recognized by AKR/G ross Mu LV-specific cytotoxic T lymphocytes [CTL]. AK7 thus pro vides the opportunity to study the role of retroviral sequence Variati ons that are located outside of the immunodominant epitope as a mechan ism of escape from CTL-mediated immune survellience. In an attempt to identify which region[s] of the AK7 genome could account for its abili ty to evade efficient recognition by AKR/Gross MuLV-specific CTL, we h ave constructed recombinant murine retroviruses. The direct influence of a sequence variation twelve amino acids N-terminal to KSPWFTTL was explored with the use of chimeric viruses and determined not to signif icantly impair the presentation or KSPWFTTL to AKR/Gross MuLV-specific CTL. The long terminal repeat [LTR] derived from the AK7 virus, which possesses only one copy of the 99-base pair transcriptional enhancer in the U3 region, in contrast to AKR623 that possesses two copies of t he tandem direct repeat enhancers, was also analyzed for its influence an the presentation of KSPWFTTL. Interestingly, our data indicate tha t the enhancer region derived from AK7 negatively influences the prese ntation of KSPWFTTL in the context of a recombinant AKR623 virus. (C) 1997 Academic Press.