High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection.
Hepatitis C virus (HCV) is an important human pathogen that represents a model for chronic infection given that the majority of infected individuals fail to clear the infection despite generation of virus-specific T cell responses during the period of acute infection. Although viral sequence evolution at targeted MHC class I-restricted epitopes represents one mechanism for immune escape in HCV, many targeted epitopes remain intact under circumstances of viral persistence. To explore alternative mechanisms of HCV immune evasion, we analyzed patterns of expression of a major inhibitory receptor on T cells, programmed death-1 (PD-1), from the time of initial infection and correlated these with HCV RNA levels, outcome of infection, and sequence escape within the targeted epitope. We show that the level of PD-1 expression in early HCV infection is significantly higher on HCV-specific T cells from subjects who progress to chronic HCV infection than from those who clear infection. This correlation is independent of HCV RNA levels, compatible with the notion that high PD-1 expression on HCV-specific CD8 T cells during acute infection inhibits viral clearance. Viral escape during persistent infection is associated with reduction in PD-1 levels on the surface of HCV-specific T cells, supporting the necessity of ongoing antigenic stimulation of T cells for maintenance of PD-1 expression. These results support the idea that PD-1 expression on T cells specific for nonescaped epitopes contributes to viral persistence and suggest that PD-1 blockade may alter the outcome of HCV infection.
Rutebemberwa
Alleluiah
A
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Ray
Stuart C
SC
Astemborski
Jacquie
J
Levine
Jordana
J
Liu
Lin
L
Dowd
Kimberly A
KA
Clute
Shalyn
S
Wang
Changyu
C
Korman
Alan
A
Sette
Alessandro
A
Sidney
John
J
Pardoll
Drew M
DM
Cox
Andrea L
AL
D000208:Acute Disease; D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000956:Antigens, Viral / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor; D011446:Prospective Studies; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D019562:Viral Load; D017735:Virus Latency / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; D018984:Epitopes, T-Lymphocyte; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral