Anti-gag cytolytic T lymphocytes specific for an alternative translationalreading frame-derived epitope and resistance versus susceptibility to retrovirus-induced murine AIDS in F-1 mice

Murine AIDS (MAIDS) develops in susceptible mouse strains after infection w ith the LP-BM5 murine leukemia virus complex that contains causative defect ive, and ecotropic helper, retroviruses. We previously demonstrated that th e MAIDS-resistant H-2(d) strains BALB/cByJ and C57BL/KsJ generate MHC class I (K-d) restricted virus-specific CD8(+) cytolytic T lymphocytes (CTLs) th at lyse cells expressing either defective or ecotropic gag proteins. In con trast, the congenic BALB.B and closely related C57BL/6J MAIDS-susceptible H -2(b) strains were unable to serve as a source of flag-specific CTLs (Schwa rz and Green, 1994), suggesting that anti-gag CTLs might provide a basis fo r resistance to MAIDS. Although its susceptibility to MAIDS was unknown, th e (BALB/c x C57BL/6J) F-1 (CBY6F(1)) strain could also produce H-2(d)-, but not H-2(b)-, restricted, anti-gag CTLs (Schwarz and Green, 1994). Because of this correlation between anti-gag CTLs and resistance to MAIDS, it was i mportant to provide more direct evidence in support of CTL-mediated protect ion and to determine both the fine specificity of CByB6F, anti-gag CTLs, in comparison with the resistant C57BL/Ks and BALB/c strains, and the suscept ibility of this F, strain to LP-BM5-induced MAIDS. We report here that no s ymptoms of MAIDS were observed in CBY6F, (H-2(dxb)) mice. For F-2 mice, in contrast to the high susceptibility of H-2(b/b) mice, 77% of H-2(d/d) and 8 1% of H-2(b/d) F-2 mice did not exhibit MAIDS after LP-BM5 infection. These results are in contrast to other published studies that concluded that sus ceptibility, rather than resistance, is dominant in F, (resistant x suscept ible or susceptible x resistant) mice. We also show that CBY6F, anti-gag CT Ls exhibit a fine specificity shared by the MAIDS-resistant BALB/c and C57B L/Ks strains, that is, the immunodominant gag epitope, SYNTGRFPPL, encoded by an alternative open reading frame. Together with our direct demonstratio n here that in vivo monoclonal antibody (mAb) depletion of CD8(+) T cells c onverts genetically resistant mice to MAIDS susceptibility, these data on t he ability to mount anti-ORF2/SYNTGRFPPL, gag-specific CTL responses strong ly 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 r esistant H-2(d) haplotype. Interestingly, however, 19% of H-2(d/b) and 23% of the H-2(d/d) F, mice had at least one clinical aspect of MAIDS, suggesti ng that a non-MHC genetic determinant(s) can negatively influence T-cell pr otection and thus disease outcome (C) 2000 Academic Press.