Immunotherapy of murine retrovirus-induced acquired immunodeficiency by CD4 T regulatory cell depletion and PD-1 blockade (154.37)

Abstract

Abstract LP-BM5 retrovirus induces a disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS) in susceptible strains of mice, such as C57BL/6 (B6). CD4 T helper effector cells are critical to MAIDS induction and progression of viral pathogenesis. CD8 T cells are not needed for viral pathogenesis, but rather are essential for protection from disease in resistant strains, such as BALB/c. We have discovered an immunodominant cytolytic T lymphocyte (CTL) epitope encoded in a previously un-recognized LP-BM5 retroviral alternative (+1 NT) gag translational open reading frame. CTLs specific for this cryptic gag epitope are the basis of protection from LP-BM5-induced immunodeficiency in BALB/c mice, and the inability of B6 mice to mount an anti-gag CTL response is critical to MAIDS pathogenesis. However, uninfected B6 mice can generate CTL responses to LP-BM5 retrovirus-associated epitope(s) especially prevalent on LP-BM5-induced tumors. Here, we utilized this LP-BM5 retrovirus-induced disease model to test whether modulation of normal immune down-regulatory mechanisms can modulate retroviral pathogenesis. Following in vivo depletion of CD4 T regulatory (Treg) cells, and/or selective interruption of PD-1 negative signaling in the CD8 T-cell compartment, retroviral pathogenesis, but not viral load, was substantially decreased, with the combined treatment of CD4 Treg depletion and PD-1 blockade working in a synergistic fashion to eliminate induction of MAIDS.