The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.

Abstract

Cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during hepatitis B virus (HBV) infection. Using a strategy involving the in vitro stimulation of peripheral blood mononuclear cells (PBMC) with HBV-derived synthetic peptides containing HLA-A2.1, -A31, and -Aw68 binding motifs, we have previously described CTL responses to several epitopes within the HBV nucleocapsid and envelope antigens in patients with acute hepatitis. In this study we define six HLA-A2-restricted CTL epitopes located in the highly conserved reverse transcriptase and RNase H domains of the viral polymerase protein, and we show that the CTL response to polymerase is polyclonal, multispecific, and mediated by CD8+ T cells in patients with acute viral hepatitis, but that it is not detectable in patients with chronic HBV infection or uninfected healthy blood donors. Importantly, the peptide-activated CTL recognize target cells that express endogenously synthesized polymerase protein, suggesting that these peptides represent naturally processed viral epitopes. DNA sequence analysis of the viruses in patients who did not respond to peptide stimulation indicated that CTL nonresponsiveness was not due to infection by viral variants that differed in sequences from the synthetic peptides. CTL specific for one of the epitopes were unable to recognize several naturally occurring viral variants, except at high peptide concentration, underlining the HBV subtype specificity of this response. Furthermore, CTL responses against polymerase, core, and envelope epitopes were detectable for more than a year after complete clinical recovery and seroconversion, reflecting either the persistence of trace amounts of virus or the presence of long lived memory CTL in the absence of viral antigen. Finally, we demonstrated that wild type viral DNA and RNA can persist indefinitely, in trace quantities, in the serum and PBMC after complete clinical and serological recovery, despite a concomitant, vigorous, and sustained polyclonal CTL response. Since viral persistence is not due to escape from CTL recognition under these conditions, the data suggest that HBV may retreat into immunologically privileged sites from which it can seed the circulation and reach CTL-inaccessible tissues, thereby maintaining the CTL response in apparently cured individuals and, perhaps, prolonging the liver disease in patients with chronic hepatitis.

Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis

“…It is conceivable that these two findings may represent the opposite sides of the same dynamic equilibrium, in which the persisting virus is kept under control through continuous elimination of infected cells by virus-specific immune responses. Vigorous HBV-specific cytotoxic T-lymphocyte reactivity demonstrated in the peripheral blood of patients years after recovery from acute hepatitis B, 3,4 suggesting sustained re-exposure of the T cells to virus antigens, could be consistent with the above interpretation. HCC ultimately developed in 2 of the 9 (22%) woodchucks within 35.5 and 56 months after apparent complete resolution of WHV infection.…”

“…[1][2][3][4][5] In these convalescent patients, HBV DNA have been detected both in serum and in circulating lymphomononuclear cells, often despite the presence of neutralizing antibodies to virus envelope (hepatitis B surface antigen) 2,3,5 and a vigorous polyclonal HBV-specific cytotoxic T-cell response. 3,4,6 In addition, traces of hepatitis B surface antigen and HBV-DNA-reactive particles with physicochemical properties of intact virions have been detected in the circulation of some of the recovered individuals. 2 These findings imply that HBV eradication does not coincide with the rise of antivirusspecific humoral and cellular immune responses and with clinical resolution of acute hepatitis.…”

Immunodominance Among EBV-Derived Epitopes Restricted by HLA-B27 Does Not Correlate with Epitope Abundance in EBV-Transformed B-Lymphoblastoid Cell Lines

“…In other persistent viral infections such as lymphocytic choriomeningitis virus (41)(42)(43), hepatitis B virus (44,45), and HIV (46,47), it has been demonstrated that virus-specific, CD8 ϩ T cells undergo repeated activation that ultimately results in activation-induced cell death (48). During a chronic EBV infection, it is possible that virus-specific CTL frequently encounter their cognate Ags on the surface of EBV-transformed B cells and that the continuous exposure of these CTL to EBV epitopes eventually results in activation-induced cell death and their disappearance from the memory T cell population.…”

MICA and recovery from hepatitis C virus and hepatitis B virus infections

“…14,15 As with HCV infection, the host immune response to HBV infection determines viral persistence, 16,17 which has been associated with polymorphisms in the human leukocyte antigen complex and other immune response genes. [18][19][20][21][22][23][24] Although there are likely important differences in the mechanisms of HBV persistence, there is also evidence that NK T (NKT) cells play an important role.…”