Liver Injury Associated with Hepatitis C Infection:
Is it the Virus or is it the Host?
Editorial by Dwain Thiel, M.D.
[Referencing: Nelson DR, Marousis CG, Davis GL, Rice CM, Wong J, Houghton M, Lau JYN. The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C. Reprinted with permission. J Immunol 1997;158:1473-1481.]
Cellular immune responses, particularly those mediated by CD8+ cytotoxic T lymphocytes (CTL), may be important in the pathogenesis and control of hepatitis C virus (Hepatitis C Virus) infection. To define the role of Hepatitis C Virus-specific CTL in chronic hepatitis C, Hepatitis C Virus-specific CTL activity in liver and peripheral blood was assessed in 35 patients with chronic Hepatitis C Virus infection and 5 non-Hepatitis C Virus controls. Hepatitis C Virus-specific CTL activity of expanding CD8+ cells was evaluated against autologous lymphoblastoid cells transduced with recombinant vaccinia virus vector expressing Hepatitis C Virus genotype 1a Ags. CTL activity was detected in unprimed bulk-expanded CD8+ cells derived from the liver in 16 of 35 patients, but not in peripheral circulation. Three patients infected with non-type 1 Hepatitis C Virus were found to have Hepatitis C Virus-specific CTL activity against Hepatitis C Virus type 1a epitopes, all directed toward Hepatitis C Virus core region. Compared with patients without detectable Hepatitis C Virus-specific CTL activity based on our assay, those showing CTL activity had lower levels of viremia (P < .01 for both branched DNA version 1.0 and 2.0 assays) and more active disease, as reflected by a higher histological activity index (P = .006) and serum alanine aminotransferase levels (P =.03). It is concluded that 1) with nonspecific stimulation, Hepatitis C Virus-specific CTL activity is found more commonly in the liver than in peripheral circulation, suggesting a tissue-specific localization with Hepatitis C Virus-specific CTL and/or its precursors; 2) cross-genotype CTL activity exists, especially toward Hepatitis C Virus core, which is relatively conserved across genotypes; and 3) patients with intrahepatic Hepatitis C Virus-specific CTL activity had lower levels of viremia and more active liver disease.
The role of the host immune response in determining clinical outcome following hepatitis B virus (HBV) infection is well recognized.1 In patients infected with hepatitis B, therapies, diseases, or conditions that impair specific lymphocyte responses lead to a high rate of chronic infection; in addition, the vigor of the host T-cell response to HBV-encoded antigenic peptides appears to correlate directly with the degree of acute hepatocellular injury and inversely with levels of HBV viremia. Moreover, low serum HBV DNA and elevated serum alanine transaminase levels, two apparent clinical manifestations of an active host immune response to HBV, are the best clinical predictors of response to interferon therapy.2,3
The natural history of hepatitis C virus (Hepatitis C Virus) infection and patterns of response to interferon therapy initially called into question the role of host immune responses in determining disease outcome. In contrast to HBV, which only occasionally leads to chronic infection in immunocompetent young adults, Hepatitis C Virus leads to chronic (>6 mo) infection in all or nearly all individuals.4 Thus, the host immune response to hepatitis C appears almost invariably to be inadequate to the task of clearing viremia during the natural course of Hepatitis C Virus infection. In contrast to interferon-induced elevations in serum aminotransferase levels that often precede clearance of serum hepatitis B e antigen and HBV DNA and seems to indicate an immune adjuvant effect of this therapy, one of the best indicators of a short- and long-term response to interferon therapy of hepatitis C infection is rapid normalization of serum aminotransferases following onset of therapy.5 These observations led many observers to hypothesize that interferon therapy modulates the course of hepatitis C largely through a direct antiviral effect with the host immune system playing a rather inconsequential bystander role. Subsequent reports that hepatitis C may run an unusually aggressive course among patients with immunoglobulin deficiency6 or the acquired immune deficiencies7 has offered additional support to the hypothesis that liver injury secondary to Hepatitis C Virus infection is mediated by direct effects of the virus rather than by host immune responses to Hepatitis C Virus-infected hepatocytes.
In the article abstracted above, Nelson et al. report findings that suggest that the level of host immune response to hepatitis C likely plays a more significant role in hepatitis C pathogenesis than was initially surmised. Previous investigators have isolated and characterized Hepatitis C Virus-specific cytotoxic T lymphocytes (CTL) present in the liver of patients with chronic Hepatitis C Virus infection.8 In their studies, Nelson and co-workers set out to use previously described techniques to assay intrahepatic and peripheral blood anti-Hepatitis C Virus specific CTL activity in a larger cohort of patients to assess whether any correlation exists between CTL activity and levels of viremia or biochemical and histological markers of hepatocellular injury. Although unable to detect anti-Hepatitis C Virus specific CTL after using non-Hepatitis C Virus specific stimuli to expand peripheral blood CD8 (+) lymphocytes, they did detect Hepatitis C Virus-specific CTL in bulk-expanded lymphocytes obtained from liver biopsy specimens in 16 of 35 patients. Of note, despite using vaccinia vectors encoding genotype 1a Hepatitis C Virus epitopes in their assays, anti-Hepatitis C Virus specific CTL activity was detected in 3 of 9 patients with genotype 1b and 3 of 9 patients with non-type 1 genotypes as well as in 10 of 17 patients with genotype 1a or mixed genotype 1a and 2a infections. Thus despite concerns that CTL responses might be underestimated because of sequence differences between in vivo viral antigens stimulating the response and the recombinant genotype 1a antigens used in in vitro research assays, sufficient CTL responses appear to be directed against conserved epitopes derived from the Hepatitis C Virus core protein to allow detection in such assays of CTL responses in patients with non-type 1a genotypes. Of even greater relevance to our understanding of the pathogenesis of chronic hepatitis C-associated liver disease, analysis of levels of serum Hepatitis C Virus RNA, serum alanine transaminase, and histological activity indices in these patients indicated a highly significant positive correlation between presence of anti-Hepatitis C Virus specific CTL and degree of alanine transaminase elevation and histological activity as well as an inverse correlation between presence of anti-Hepatitis C Virus specific CTL and levels of viremia. These findings suggest that not only are anti-Hepatitis C Virus specific CTL responses elicited during the course of this infection, but the level of the response correlates with and therefore might be responsible for much of the ongoing acute hepatocellular injury observed during the course of this disease. Moreover, as has been suggested in multiple other viral infections, even when anti-host responses are unable to completely eradicate a virus such as Hepatitis C Virus, anti-viral CTL responses still appear to play an important role in controlling levels of viremia.
Although Nelson et al. were able to detect correlations between anti-Hepatitis C Virus specific CTL responses and markers of hepatocellular injury in an analysis that included only 35 patients, it seems almost certain that much larger studies will be required to determine whether there is a direct correlation between anti-Hepatitis C Virus specific CTL responses and disease outcome or response to interferon therapy. Nevertheless, the presently abstracted findings in conjunction with a series of additional clinical observations already suggest that host anti-Hepatitis C Virus specific immune responses almost certainly do play a role in course of Hepatitis C Virus-associated liver disease and response to therapy. Thus, there is increasing evidence that at least a small subset of individuals infected with hepatitis C do manage to eventually clear the infection without therapeutic intervention9 whereas another subset of patients appears to achieve this highly desirable endpoint after courses of interferon therapy.5 Viral load has come to be recognized as the single best predictor of response to interferon therapy.5 If, as suggested by the currently reviewed findings, anti-Hepatitis C Virus specific CTL play a major role in suppressing viremia, then it logically follows that the presence of a host anti-Hepatitis C Virus CTL response is likely to be an important component of successful outcome following this form of therapy. Despite the well recognized genetic diversity among the various Hepatitis C Virus genotypes as well as the diversity within "quasispecies" of Hepatitis C Virus isolated from a single patient, a significant component of the host CTL response to this virus appears to be directed at highly conserved epitopes within the nucleocapsid or core protein of Hepatitis C Virus. Thus, while prospects for a traditional vaccine designed to elicit neutralizing antibodies to Hepatitis C Virus envelope proteins appear to be poor,10 perhaps there is reason to be more optimistic about vaccines or immunoadjuvant therapies designed to elicit host anti-Hepatitis C Virus specific CTL.
DWAIN L. THIELE, M.D. Liver Unit/Internal Medicine UT Southwestern Medical Center at Dallas, Dallas, TX