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

Abstract

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 type, 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 p 15E 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 gag 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.

The Level of Virus-Specific T-Cell and Macrophage Recruitment in Porcine Reproductive and Respiratory Syndrome Virus Infection in Pigs Is Independent of Virus Load

“…Although PRRSV encodes at least three proteases (70), a viral protease may not inhibit IFN signaling in infected macrophages. At least 19 genes, including the IFN-inducible gene Mx1 (29), are increased in macrophages by PRRSV infection (60), suggesting that PRRSV elicits an IFN-mediated response but may utilize other mechanisms for evasion of cellular immunity, such as down-regulation of major histocompatibility complex class I (25) or costimulatory molecule expression (27). The absence of an IFN response in lungs of acutely infected pigs (62) suggests that the IFN response observed in macrophages infected in vitro does not occur in vivo.…”

Cytolytic CD8+ T Cells Directed against a Cryptic Epitope Derived from a Retroviral Alternative Reading Frame Confer Disease Protection

“…Pathogens continually challenge the immune system by developing immune evasion mechanisms, including sequence variation within and around epitopes (3)(4)(5). CD8 T cells must be able to circumvent this problem, presumably in part by better detection.…”

“…Atypical CTL epitopes may potentially derive from all levels of gene and protein expression, including alternative reading frames (ARFs), 3 which are of particular interest to our studies (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Our laboratory has previously demonstrated that normally resistant BALB/c mice depleted of CD8 T cells by anti-CD8 mAb treatment in vivo were rendered susceptible to LP-BM5 retrovirus infection, thus showing CD8 ϩ T lymphocytes to be necessary for disease resistance (17).…”

Naturally Occurring TAP-Dependent Specific T-Cell Tolerance for a Variant of an Immunodominant Retroviral Cytotoxic T-Lymphocyte Epitope

“…C57BL/6 mice (H-2 b ) have a low incidence of spontaneously occurring thymic leukemias (relative to AKR mice [H-2 k ]) and characteristically generate vigorous H-2K b -restricted CTL responses directed against tumor cells induced by AKR/Gross murine leukemia retroviruses (MuLV), the retroviruses that are carried in the genome of AKR mice or derived by recombination from these proviruses (8,9,12). Such CTLs (designated AKR/Gross MuLV-specific CTLs) predominantly recognize a determinant (KSPWFTTL) (10,11,27,30) located within the p15E transmembrane region of the viral envelope protein. This determinant is present in nearly all endogenous ecotropic MuLV examined (4) and several mink cell focusinducing (MCF) MuLV (3,27).…”