Anti-gag cytolytic T lymphocytes specific for an alternative translational reading frame-derived epitope and resistance versus susceptibility to retrovirus-induced murine AIDS in F1 mice

Abstract

Murine AIDS (MAIDS) develops in susceptible mouse strain after infection with the LP-BM5 murine leukemia virus complex that contains causative defective, and ecotropic helper, retroviruses. We previously demonstrated that the MAIDS-resistant H-2b strains BALB/cByJ and C57BL/KsJ generate MHC class I (K(d)) restricted virus-specific CD8+ cytolytic T lymphocytes (CTLs) that lyse cells expressing either defective or ecotropic gag proteins. In contrast the congenic BALB.B and closely related C57BL/6J MAIDs-susceptible H-2b strains were unable to serve as a source of gag-specific CTLs (Schwarz and Green, 1994), suggesting that anti-gag CTLs might provide a basis for resistance to MAIDS. Although its susceptibility to MAIDS was unknown, the (BALB/c x C57BL/6J) F1 (CBY6F1) strain could also produce H-2(d)-, but not H-2b-, restricted, anti-gag CTLs (Schwarz and Green, 1994). Because of this correlation between anti-gag CTLs and resistance to MAIDS, it was important to provide more direct evidence in support of CTL-mediated protection and to determine both the fine specificity of CByB6F1 anti-gag CTLs, in comparison with the resistant C57BL/Ks and BALB/c strains, and the susceptibility of this F1 strain to LP-BM5-induced MAIDS. We report here that no symptoms of MAIDS were observed in CBY6F1 (H-2(dxb)) mice. For F2 mice, in contrast to the high susceptibility of H-2(b/b) mice, 77% of H-2(d/d) and 81% of H-2(b/d) F2 mice did not exhibit MAIDS after LP-BM5 infection. These results are in contrast to other published studies that concluded that susceptibility, rather than resistance, is dominant in F1 (resistant x susceptible or susceptible x resistant) mice. We also show that CBY6F1 anti-gag CTLs exhibit a fine specificity shared by the MAIDS-resistant BALB/c and C57BL/Ks strains, that is, the immunodominant gag epitope, SYNTGRFPPL, encoded by an alternative open reading frame. Together with our direct demonstration here that in vivo monoclonal antibody (mAb) depletion of CD8+ T cells converts genetically resistant mice to MAIDS susceptibility, these data on the ability to mount anti-ORF2/SYNTGRFPPL, gag-specific CTL response strongly suggest that CTLs are a primary factor in determining MAIDS resistance. Accordingly, given the K(d)-restricted nature of the CTLs, the main genetic determinant of resistance appeared to be the codominant expression of the resistant H-2(d) haplotype. Interestingly, however, 19% of H-2(d/b) and 23% of the H-2(d/d) F2 mice had at least one clinical aspect of MAIDS, suggesting that a non-MHC genetic determinant(s) can negatively influence T-cell protection and thus disease outcome. (C) 2000 Academic Press.