Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy

Abstract

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, end-stage liver disease, and hepatocellular carcinoma throughout the world. Considerable evidence indicates that the risk of viral persistence, natural history, and response to antiviral therapy varies among racial groups, but limited data exist on potential mechanisms to account for these differences. Type 1 helper (Th1) responses to HCV proteins and cytomegalovirus (CMV) antigens were examined using a sensitive interferon (IFN)-␥ enzyme-linked immunospot (ELISPOT) assay in 187 Caucasian American (CA) and 187 African American (AA) patients with chronic genotype 1 infection. ELISPOT responses were examined relative to human leukocyte antigen (HLA) class II alleles and outcome of therapy with pegylated IFN and ribavirin. Th1 responses specific to hepatitis C core protein and combined HCV antigens were significantly lower in AAs compared to CAs, but CMV responses were comparable in the 2 races. The HCV difference in immunity remained after adjusting for gender, serum alanine aminotransferase, histologic severity, and viral level, and was not accounted for by the differential prevalence of human leukocyte antigen class II alleles. Pretreatment total HCV-specific CD4؉ T cell response was associated with sustained virologic response (SVR) to pegylated IFN and ribavirin; 43% of patients who had more than 168 ELISPOTs/10 6 peripheral blood mononuclear cells (above background) experienced SVR compared to 28% of those who did not (P ‫؍‬ 0.007). ELISPOT response was independently associated with SVR by multivariable analysis. Conclusion: Compared to CAs, AAs have weaker HCVspecific immunity. Pretreatment HCV-specific immunity is associated with response to combination antiviral therapy. (HEPATOLOGY 2007;46:350-358.)

Retention of CD4 + CD25 + FoxP3 + Regulatory T Cells in the Liver after Therapy-Induced Hepatitis C Virus Eradication in Humans

“…Studies using intrahepatic cells are difficult to perform since liver biopsy samples are collected from patients for diagnostic purposes only and are therefore limited to pretreatment assessment of liver cells. The findings of these studies indicate that baseline intrahepatic CD8 ϩ T cell responses in chronic HCV patients are important for successful response to IFN-␣-based therapy (7,9,12), which is in line with reports on peripheral blood T cells (14,17). However, it remains unclear how intrahepatic immunity is affected by IFN-␣-based therapy and how this contributes to treatment outcome.…”

Treatment responses in Asians and Caucasians with chronic hepatitis C infection

“…It was also noted that African Americans had different pretreatment cytokine profiles [30] . In addition, while they mounted a more robust HCV-specific CD4 Th1 proliferative response, it did not translate into a higher rate of IFN-gamma production, potentially secondary to their dysfunctional nature, which was associated with a failure of interferon therapy [31][32] . The significance of these studies is that the impact of ethnicity, on treatment response is more likely to be related to host factors, particularly to genetic differences in immune regulation rather than environmental factors.…”

Emerging concepts in immunity to hepatitis C virus infection

“…NKp30, which is induced by IL-2, is most highly expressed on the NK and NKT cells of exposed, uninfected subjects (70). The NKp46 receptor is considered the major human natural cytotoxicity receptor involved in NK cell-mediated killing (72,73) and is more highly expressed on the NK cells of women and people of mixed European descent (i.e., populations known to demonstrate higher rates of spontaneous resolution of HCV infection) (74)(75)(76). NKp46 ligand expression is induced on hepatocytes following HCV infection (76), although whether this represents a specific HCV component or an unspecific stress response is not yet clear.…”