Antonio Bertoletti

Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection.

Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections

BACKGROUND & AIMSnThe cytokine pattern secreted by T cells at the site of viral replication may influence the final outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The aim of this study was to assess whether a cytokine imbalance oriented toward T helper (Th) 1 or Th2-type responses may play a role in chronic hepatitis B or C.nnnMETHODSnProduction of interferon (IFN)-gamma, interleukin (IL)-4, and IL-5 by wide series of T-cell clones derived from the liver of 6 patients with chronic hepatitis B (291 clones) and 9 patients with chronic hepatitis C (260 clones) was studied. T-cell clones were generated by limiting dilution from freshly isolated mononuclear cells derived from liver tissue to give a reliable representation of the intrahepatic inflammatory infiltrates.nnnRESULTSnThe majority of liver-infiltrating T cells in chronic hepatitis C were Th1 cells able to secrete IFN-gamma but unable to secrete IL-4 or IL-5, whereas in hepatitis B, most CD4+ and CD8+ liver T cells were ThO-like cells able to produce not only IFN-gamma but also IL-4 and IL-5.nnnCONCLUSIONSnThe different cytokine profiles of T cells within the liver in chronic HBV and HCV infections illustrate a different behavior of the local immune response in these two infections that may have pathogenetic implications.

Long-lasting memory T cell responses following self-limited acute hepatitis B.

The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO+T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects. to conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control.

Cell mediated immune response to hepatitis B virus nucleocapsid antigen

A coordinated and efficient development of humoral and cell-mediated immune responses is believed to be required for complete eradication of viral infections. During the course of hepatitis B virus (HBV) infection, the HLA class II and class I-restricted T cell responses to HBV nucleocapsid antigens are vigorous in patients with acute infection who succeed in clearing the virus but weak or totally absent in patients with chronic persistence of the virus. These findings suggest a role for these responses in the pathogenesis of hepatitis B and in HBV clearance. Molecular analysis of T cell recognition of the HBV nucleoprotein defines the presence of immunodominant core epitopes recognized by helper and cytotoxic T cells that may represent the starting point for the design of alternative strategies for prevention and treatment of HBV infection.

The Role of the Cytotoxic T Lymphocyte Response in Hepatitis B Virus Immunobiology and Pathogenesis

During the past few years we have witnessed the dawning of a new era in hepadnavirus immunobiology, thanks to remarkable insights that have recently been gained into the molecular basis for antigen recognition, and to the development of synthetic and recombinant technology to produce epitope analogs, transfected target cells, and transgenic mice that have made the strides described in this report possible. The outcome of these advances will lead to a comprehensive understanding of the immunobiology and pathogenesis of HBV infection and, indeed, of any virus whose genome has been cloned and sequenced. The same holds true, in fact, for any pathogen, indeed for any antigen, including tumor antigens, that one might wish to study. Based on these concepts, discoveries similar to those described herein could lead to T cell-based vaccines for some of these pathogens. They may also permit the development of novel immunotherapeutic strategies for termination of chronic viral diseases such as those caused by HBV, HCV, and HIV, and perhaps even cancer as well. Not surprisingly, such efforts are already underway.

Cell-mediated Immune Response in Hepatitis C Virus (HCV) Infection: Are Different Strategies Adopted by HCV and Hepatitis B Virus to Persist?

Immune-mediated mechanisms play an important role in the pathogenesis of liver cell injury and viral persistence in both HCV and hepatitis B virus (HBV) infections. However, the different vigor of HLA class I and class II restricted, anti-viral T cell responses in chronic hepatitis C and B and the different cytokine profiles within HCV and HBV infected livers suggest that these hepatotropic viruses have evolved different strategies to persist within their hosts and that different pathogenetic mechanisms are operative during HCV and HBV infections.

Role of the cell-mediated immune response in the pathogenesis of hepatitis B virus infection

Hepatitis B virus (HBV) infection usually leads to self-limited acute hepatitis with complete recovery of the patients and clearance of the virus from the circulation. However some patients (5 to 10%) do not clear the virus and they become chronic carriers, with or without evidence of liver disease. The sequence of events leading to clearance or persistence of HBV in the infected organism are still largely unknown. Based on available data derived from studies in HBV and in other viral systems, it is generally assumed that a human leucocyte antigen (HLA) class I-restricted cytotoxic T lymphocyte (CTL) response to one or more HBV-encoded antigens displayed at the hepatocyte membrane is a major effector mechanism of hepatocellular injury and clearance of infected cells. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic strategies to terminate chronic HBV infection.