Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape

Mouse retrovirus-induced lymphoma/leukemia and immunodeficiency are useful models for analogous human diseases. Both ecotropic (mouse tropic) and recombinant retroviruses, including the polytropic mink cytopathic focus-inducing ripe, have been studied for disease pathogenesis and as targets for humoral and cellular immunity, particularly cytotoxic T-lymphocyte (CTL) responses. For AKR/Gross murine leukemia viruses (MuLV) we have defined an immunodominant CTL epitope in the p15E transmembrane anchor envelope protein and three minor/subdominant epitopes. Evidence is presented for retroviral escape from CTL by selection following genetic recombination and point mutation both within and outside CTL epitope sequences, and via endogenous retrovirus-infected cell downregulation of the generation of anti-AKR/Gross MuLV CTL. As demonstrated in vivo in naturally occurring non-responder strains by adoptive transfer, and in vitro by cell-mixing experiments, a central non-responsiveness mechanism appears to be peripheral inhibition mediated by infected cells expressing MHC-presented viral peptides. Such inhibition requires Fas expression by antiviral T cells; occurs upon TCR-mediated recognition of virus-infected, Fas ligand-expressing "veto" cells; and apparently leads to an antigen-specific form of activation-induced cell death of T cells. In the LP-BM5 MuLV isolate that causes murine AIDS (MAIDS) retroviral variation also leads to CTL escape - the BM5-helper virus has altered forms of the immunodominant and two minor/subdominant epitopes. In contrast, a novel immunodominant CTL epitope is recognized by MAIDS-resistant, but not MAIDS-susceptible, strains. This epitope is uniquely encoded in an alternative translational reading frame of the viral sag gene. It also appears that the LP-BM5 MuLV have co-opted the cells of the immune system for retroviral pathogenesis - CD40/CD40L (CD154) interactions are required both for the initiation and progression of MAIDS.