title: Immunotherapy of murine retrovirus-induced acquired immunodeficiency by CD4 T regulatory cell depletion and PD-1 blockade.
abstract: LP-BM5 retrovirus induces a complex 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 required for 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 unrecognized LP-BM5 retroviral alternative (+1 nucleotide [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 appears critical to the initiation and progression of LP-BM5-induced MAIDS. However, uninfected B6 mice primed by LP-BM5-induced tumors can generate CTL responses to an LP-BM5 retrovirus infection-associated epitope(s) that is especially prevalent on such MAIDS tumor cells, indicating the potential to mount a protective CD8 T-cell response. Here, we utilized this LP-BM5 retrovirus-induced disease system to test whether modulation of normal immune down-regulatory mechanisms can alter retroviral pathogenesis. Thus, 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 was significantly decreased, with the combined treatment of CD4 Treg cell depletion and PD-1 blockade working in a synergistic fashion to substantially reduce the induction of MAIDS.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA. Wen.Li@dartmouth.edu
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: William R
authors.initials: WR
authors.lastname: Green
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods*; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000628:therapy* / Q000821:virology; D061026:Programmed Cell Death 1 Receptor; D012190:Retroviridae / Q000276:immunology / Q000472:pathogenicity*; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor