In vivo blockade of the programmed cell death-1 pathway using soluble recombinant PD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit.
The programmed cell death-1 (PD-1)/programmed cell death ligand-1 pathway has been shown to limit cell-mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell polyfunctionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD-1 fused to a macaque Ig-Fc (rPD-1-Fc) in SIVmac239-infected rhesus macaques during the early chronic phase of infection, either alone or in combination with antiretroviral therapy. In vitro blockade showed improvement of Ag-specific CD4(+) and CD8(+) T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-d blockade in culture was beneficial for both gag-specific CD4(+) and CD8(+) T cells based on proliferation and dual cytokine production. Although the in vivo administration of rPD-1-Fc induced enhanced SIV-specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of antiretroviral therapy interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001(+) monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9(+) CD8(+) T cells in the blood and rectal mucosa and polyfunctionality of GagCM9(+) CD8(+) T cells in blood. In conclusion, however, our data suggest that PD-1/programmed cell death ligand-1 blockade using soluble rPD-1-Fc instead of anti-PD-1 mAb, although effective in rescuing the effector function of SIV-specific CD4(+) and CD8(+) T cells during the early chronic phase of infection, has limited clinical benefit.
Division of Pathology, Yerkes National Primate Research Center, Atlanta, GA 30329.
Praveen K
PK
Amancha
Jung Joo
JJ
Hong
Kenneth
K
Rogers
Aftab A
AA
Ansari
Francois
F
Villinger
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D000068679:Emtricitabine / Q000031:analogs & derivatives; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007111:Immunity, Cellular; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D007167:Immunotherapy; D008222:Lymphokines / Q000378:metabolism; D008253:Macaca mulatta; D063065:Organophosphonates / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D012995:Solubility; D000068698:Tenofovir; D014766:Viremia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D044966:Anti-Retroviral Agents; D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D008222:Lymphokines; D063065:Organophosphonates; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral; D011994:Recombinant Proteins; D016047:Zalcitabine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C075889:Racivir