Recognition of endogenous ecotropic murine leukaemia viruses by anti-AKR/Gross virus cytotoxic T lymphocytes (CTL): epitope variation in a CTL-resistant virus

Abstract

AKR/Gross virus-specific cytotoxic T lymphocytes (CTL) from C57BL/6 (B6) mice are H-2Kb-restricted and recognize epitopes encoded by the prototype endogenous ecotropic routine leukaemia virus (Emv) AKR623. Four CTL epitopes have been identified by the use of synthetic peptides corresponding to AKR623-encoded amino acid sequences. Here we present both functional and nucleotide sequence data indicating that three closely related Emv share all of these CTL epitopes. We also found that one other murine leukaemia virus (MuLV) was not susceptible to lysis by these CTL. This is the ecotropic component of the LP-BM5 virus complex that causes routine AIDS. Nucleotide sequencing revealed that three of the four epitopes, including the immunodominant peptide, are altered in this virus. The other epitope was unchanged. These data implied that the inability of anti-AKR/Gross virus CTL to lyse cells infected with the LP-BM5 ecotropic (BM5eco) MuLV was due to the functional loss of three of the four CTL epitopes. Using recombinant vaccinia and Sindbis virus vectors, we have shown that the BM5eco-encoded form of the immunodominant epitope, which differs only by an arginine for lysine substitution at the N-terminal residue, fails to induce a CTL response in B6 mice. Immunization with BM5eco-infected cells also failed to induce MuLV-specific CTL. In light of the long in vivo passage history of the LP-BM5 complex in B6 mice, our results are consistent with a contribution of CTL-mediated immune selection to the evolution of the BM5eco MuLV.

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

“…1) or (C57BL/6 ϫ 129/Sv)F 1 TAP ϩ/ϩ origin as discussed above, the CTLs raised against RSPWFTTL were not broadly reactive. As expected from our previous studies (4,17) and the data of Fig. 1 and 3, synthetic RSPWFTTL peptide-restimulated splenocytes from normal C57BL/6 mice immunized with Vac 13ss failed to generate CTLs that recognized Vac 13ss-infected (Fig.…”

“…Alternatively, emv-2 sequences may contribute to the formation, in C57BL/6 mice, of other ecotropic or polytropic infectious recombinant MuLV that express RSPWFTTL. For example, our laboratory has reported that the BM5 ecotropic helper MuLV (i.e., from the LP-BM5 retroviral complex that causes murine AIDS), which originates from C57BL/6 mice, expresses the RSPWF TTL epitope (4). Other endogenous MuLV may serve as a source of expressed RSPWFTTL.…”

“…Interestingly, the only CTL line induced by the synthetic RSPWFTTL preparation proved to recognize a minor contaminant present in the preparation. The poor immunogenicity of RSPWFTTL was confirmed by expression as minigene cytosolic or ER-targeted gene products expressed by recombinant vaccinia virus (rVV) or Sindbis virus vectors that were used to immunize mice (4,17).…”

A Single Amino Acid Variation Within an Immunodominant AKR/Gross MuLV Cytotoxic T-Lymphocyte Epitope Leads to a Loss in Immunogenicity

“…In contrast, C57BL/6 (H-2b) mice have a much lower incidence of spontaneously occurring thymic lymphomas and are capable of generating vigorous AKR/Gross MuLV-specific H-2Kb-restricted CTL (30). These C57BL/6-derived AKR/Gross MuLV-specific CTL are directed against an immunodominant T-cell epitope (KSPWFTTL, also referred to as peptide 12) located at amino acid position 134-141 in the p 15 transmembrane region (TM) of the envelope protein (29,56,65) in almost all emv studied (14) and many MCF MuLV (13,56).…”

Impaired Generation of Anti-AKR/Gross Murine Leukemia Virus Cytotoxic T Lymphocytes in Mice Experimentally Infected with MuLV

“…These antiviral CTL are Kb restricted (13) and typespecific in that tumors induced by the Friend-Moloney-Rauscher (FMR) group of MuLV are recognized poorly, if at all (7). AKR/Gross MuLV-specific CTL also recognize and lyse fibroblast target cells expressing Kb and infected by several MuLV derived from endogenous proviruses, including the AKR623 molecular clone (4,12,33). Further studies have identified an immunodominant epitope located at amino acids 134-141 of the transmembrane envelope protein pl5E KSPWFTTL] (3,27,33).…”