Role of immunoproteasome catalytic subunits in the immune response to hepatitis B virus.
Inhibition of hepatitis B virus (HBV) replication and viral clearance from an infected host requires both the innate and adaptive immune responses. Expression of interferon (IFN)-inducible proteasome catalytic and regulatory subunits correlates with the IFN-alpha/beta- and IFN-gamma-mediated noncytopathic inhibition of HBV in transgenic mice and hepatocytes, as well as with clearance of the virus in acutely infected chimpanzees. The immunoproteasome catalytic subunits LMP2 and LMP7 alter proteasome specificity and influence the pool of peptides available for presentation by major histocompatibility complex class I molecules. We found that these subunits influenced both the magnitude and specificity of the CD8 T-cell response to the HBV polymerase and envelope proteins in immunized HLA-A2-transgenic mice. We also examined the role of LMP2 and LMP7 in the IFN-alpha/beta- and IFN-gamma-mediated inhibition of virus replication using HBV transgenic mice and found that they do not play a direct role in this process. These results demonstrate the ability of the IFN-induced proteasome catalytic subunits to shape the HBV-specific CD8 T-cell response and thus potentially influence the progression of infection to acute or chronic disease. In addition, these studies identify a potential key role for IFN in regulating the adaptive immune response to HBV through alterations in viral antigen processing.
Robek
Michael D
MD
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. michael.robek@yale.edu
Garcia
Mayra L
ML
Boyd
Bryan S
BS
Chisari
Francis V
FV
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015686:Gene Products, env / Q000276:immunology / Q000378:metabolism*; D015684:Gene Products, pol / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006367:HeLa Cells; D006509:Hepatitis B / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014779:Virus Replication
D015686:Gene Products, env; D015684:Gene Products, pol; D015789:HLA-A2 Antigen; D009097:Multienzyme Complexes; C071313:LMP-2 protein; D007371:Interferon-gamma; D007372:Interferons; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex