Enhancing SIV-specific immunity in vivo by PD-1 blockade.
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.
Velu
Vijayakumar
V
Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Titanji
Kehmia
K
Zhu
Baogong
B
Husain
Sajid
S
Pladevega
Annette
A
Lai
Lilin
L
Vanderford
Thomas H
TH
Chennareddi
Lakshmi
L
Silvestri
Guido
G
Freeman
Gordon J
GJ
Ahmed
Rafi
R
Amara
Rama Rao
RR
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
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D051017:Apoptosis Regulatory Proteins; D015683:Gene Products, gag