HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen.

Abstract

HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen (viral pathogenesis/viral ABSTRACTKnowledge of the immune effector mechanisms responsible for clearance of hepatitis B virus (HBV)-infected cells has been severely limited by the absence of reproducible systems to selectively expand and to characterize HBV-specific cytotoxic T lymphocytes (CTLs) in the peripheral blood of patients with viral hepatitis. By using a strategy involving sequential stimulation with HBV nucleocapsid synthetic peptides followed by autologous, or HLA class I-matched, HBV nucleocapsid transfectants, we now report the existence of CTLs able to lyse target cells that express endogenously synthesized HBV nucleocapsid antigen in the peripheral blood of patients with acute viral hepatitis B. The CTL response is HLA-A2 restricted, mediated by CD8-positive T cells, and specific for a single epitope, located between amino acid residues 11 and 27 of HBV core protein; these residues are shared with the secretable precore-derived hepatitis B e antigen. Equivalent lysis of target cells that express each of these proteins suggests that their intracellular trafficking pathways may intersect. The current report provides definitive evidence that HLA class I-restricted, CD8-positive CTLs that recognize endogenously synthesized HBV nucleocapsid antigen are induced during acute HBV infection in humans and establishes a strategy that should permit a detailed analysis of the role played by HBV-specific CTLs in the immunopathogenesis of viral

Novel pre-C/C gene mutants of hepatitis B virus in chronic active hepatitis: naturally occurring escape mutants

“…Sequencing products were separated on 6 % acrylamide-urea gels. Nucleotide sequence mutations in known B cell epitopes (amino acids 74~89, 130-138 and 107-118), CD4 + helper T cell epitopes (amino acids 1-20, 50-69 and 117-131; Nayersina et al, 1993 ;Bertoletti et al, 1991) and HLA-restricted CTL epitopes (18 27 and 141 151) of the core region were determined and analysed Nassal et al, 1992). Besides these, the nucleotide sequence of the arginine-rich C-terminal region of the core, which is important for pregenomic RNA encapsidation (amino acids 150-154) and HBV DNA synthesis (158-171), was determined and analysed (Nassal & Rieger, 1993).…”

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

“…This type of CTL response is unusual, however, during HBV infection, when the CTL response is typically vigorous and multispecific during acute hepatitis and weak or undetectable during chronic hepatitis. 42,65,66,72 Accordingly, mutational inactivation of CTL epitopes is extremely uncommon during chronic HBV infection. 73 Nonetheless, strong, narrowly focused CTL responses do occur occasionally in these patients, 20 and in this setting viral escape mutations can occur.…”

The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection

“…The HBeAg has a suppressive effect on T cells, and in particular, because most of the primary sequence of HBeAg is shared by core, it is plausible that circulating HBeAg may prevent cytotoxic T lymphocytes (CTLs) from recognizing infected hepatocytes which expose core-derived peptides on their surfaces. Most CTLs responsible for the hepatocyte injury in HBV infection are known to be directed to core-derived peptides (Mondelli et al, 1982;Bertoletti et al, 1991). The slight downward shift, induced by the evolution of the mutant, of the relative amount of HBeAg compared to that of core thus creates a partial liberation of core-specific CTLs from the long-standing suppression exerted by circulating HBeAg, so a greater number of infected hepatocytes would be recognized by CTLs and eventually undergo apoptosis.…”