title: Enhancing SIV-specific immunity in vivo by PD-1 blockade.
abstract: Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1) during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late ( approximately week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections.
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.forename: Kehmia
authors.initials: K
authors.lastname: Titanji
authors.forename: Baogong
authors.initials: B
authors.lastname: Zhu
authors.forename: Sajid
authors.initials: S
authors.lastname: Husain
authors.forename: Annette
authors.initials: A
authors.lastname: Pladevega
authors.forename: Lilin
authors.initials: L
authors.lastname: Lai
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Vanderford
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Chennareddi
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes; D015683:Gene Products, gag / Q000097:blood; D007113:Immunity, Innate / Q000187:drug effects*; D007422:Intestines / Q000187:drug effects / Q000276:immunology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D016019:Survival Analysis; D014766:Viremia / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D051017:Apoptosis Regulatory Proteins; D015683:Gene Products, gag