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Virology - Research and Treatment


Geisel School of Medicine


Murine AIDS (MAIDS) develops in susceptible mouse strains after infection with the LP-BM5 murine leukemia virus complex that contains causative defective, and ecotropic helper, retroviruses. We previously demonstrated that the MAIDSresistant H-2d strains BALB/cByJ and C57BL/KsJ generate MHC class I (Kd ) restricted virus-specific CD81 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 3 C57BL/6J) F1 (CBY6F1) strain could also produce H-2d -, 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-2d3b ) mice. For F2 mice, in contrast to the high susceptibility of H-2b/b mice, 77% of H-2d/d and 81% of H-2b/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 3 susceptible or susceptible 3 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 CD81 T cells converts genetically resistant mice to MAIDS susceptibility, these data on the ability to mount anti-ORF2/SYNTGRFPPL, gag-specific CTL responses strongly suggest that CTLs are a primary factor in determining MAIDS resistance. Accordingly, given the Kd -restricted nature of the CTLs, the main genetic determinant of resistance appeared to be the codominant expression of the resistant H-2d haplotype. Interestingly, however, 19% of H-2d/b and 23% of the H-2d/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.