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 strains 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-2(d) 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-2(b) 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) 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 important to provide more direct evidence in support of CTL-mediated protection and to determine both the fine specificity of CByB6F(1) anti-gag CTLs, in comparison with the resistant C57BL/Ks and BALB/c strains, and the susceptibility of this F(1) strain to LP-BM5-induced MAIDS. We report here that no symptoms of MAIDS were observed in CBY6F(1) (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 81% 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 susceptibility, rather than resistance, is dominant in F(1) (resistant x susceptible or susceptible x resistant) mice. We also show that CBY6F(1) 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 responses 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) F(2) 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

Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency

“…+ PD-1 + T cells is limited, T cell proliferative responses maintained, and viral replication better controlled in the RIAD-transgenic mice. The latter finding is particularly interesting and does suggest that maintained T cell function indeed contributes to improved viral control in MAIDS, a thought also supported by a report showing that CTL play a crucial role in the resistance of some mice strains to LP-BM5 infection (59). Some steps in the viral cycle may depend on PKA activity.…”

The Programmed Death-1 and Interleukin-10 Pathways Play a Down-Modulatory Role in LP-BM5 Retrovirus-Induced Murine Immunodeficiency Syndrome

“…In disease-resistant BALB/c mice, however, we have shown that CD8-deficient (chronic in vivo anti-CD8 MAb treated or CD8 KO) mice convert to disease susceptibility (27,45) and that WT BALB/c mice generate a strong antiviral CD8 ϩ T-cell response (63). Indeed, the BALB/c CD8 ϩ T effector cells are highly lytic, secrete IFN-␥, and are protective against LP-BM5 virus challenge in vivo, in terms of both inhibition of disease and the ultimate viral load, after their adoptive transfer into BALB/c.…”

“…CD8 KO recipients (27,44). Of note, both the polyclonal and clonal CD8 ϩ T-cell populations that were protective were specific for a unique K d -presented immunodominant epitope, SYNTGRFPPL, which derives from a previously unrecognized alternative (ϩ1 nucleotide) gag translational open reading frame of the LP-BM5 retrovirus (44,45). In contrast, the same immunization approaches with LP-BM5 virus or viral gag vector expression systems were unable to raise LP-BM5 virus-specific CD8 ϩ cytotoxic T lymphocytes in B6, BALB.B congenic, or other H-2 b susceptible mice (45,63).…”

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

“…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). The retrovirus complex, comprised of a mixture of replication-incompetent defective/pathogenic (BM5def) and replication-competent ecotropic helper (BM5eco) viruses, induces a disease termed murine AIDS (MAIDS), featuring early nonspecific B and T cell activation and proliferation, and a subsequent progressive immunodeficiency (18 -20).…”