In 1989, hepatitis C virus (HCV) was first identified as the infectious agent responsible for human non-A, non-B hepatitis. Two decades later, HCV remains a global public health problem with a suboptimal response rate to treatment and the absence of a protective vaccine. Recent work has highlighted the influence of the innate immune system, and in particular natural killer cells, on the outcome and pathology of HCV infection. These cells are considerably more complex than was originally thought and their role in viral infections is currently being unravelled. This review summarises our emerging understanding of natural killer cells in HCV infection.
"NK cells can also lyse HCV-infected hepatocytes, T cells, and APCs and modulate immune responses . However, HCV itself has been revealed to have a role in the potential inhibition of NK cell function, resulting in chronic hepatitis . "
[Show abstract][Hide abstract] ABSTRACT: Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV) reinfects transplanted livers at a rate of >90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C.
"Distinct combinations of specific killing inhibitory receptors (KIR), specific HLA class I molecules and their respective ligands were associated with either spontaneous clearance or chronicity of acute HCV infection , . Moreover, NK cell phenotype and function have been shown to be altered both in acute and chronic hepatitis C ,  and linked with either outcome of acute infection – or response to antiviral therapy –. "
[Show abstract][Hide abstract] ABSTRACT: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown.
Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells.
Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load.
PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.
PLoS ONE 04/2014; 9(4):e94512. DOI:10.1371/journal.pone.0094512 · 3.23 Impact Factor
"On the contrary, NK cells were found to be suppressed by HCV proteins (Cheent and Khakoo 2011; Varchetta et al. 2012; Wen et al. 2008). Their frequencies in peripheral blood are reduced in chronic HCV infections (Cheent and Khakoo 2011). It has been postulated that direct cell-to-cell contact of NK cells with infected hepatocytes inhibits cytotoxicity of these cells (Yoon et al. 2011). "
[Show abstract][Hide abstract] ABSTRACT: Chronic viral hepatitis C still remains the clinical challenge. Attempts of the immune system to cope with this infection are unsatisfactory. There
is a conviction that the main site of interaction between virus (Hepatitis C virus, HCV) and immune system is in situ, i.e., in liver. Natural killer (NK) cells appeared relevant in the acute hepatitis. Less is known about the immune response in the chronic HCV infection. The aim of this study was to evaluate the prevalence of various cytotoxic cell subsets in chronic HCV+ liver tissue and to seek links between them and laboratory data of patients. Sections from paraffin blocks of liver biopsy tissues of HCV+ untreated patients were subjected to the reaction with antibodies vs. cytotoxic cell subsets and immunohistochemistry. Positive cells were searched in cellular infiltrates in portal areas and in liver parenchyma. They were classified on the “Yes” or “No” basis. Majority of liver biopsies exhibited cellular infiltrates in portal spaces and as single cells in liver parenchyma. Infiltrates consisted of CD8+ T cells, CD56+ NK ones, including CD158i+ and CD158b+. The latter were rarely seen. There were also granzyme B+ cells. The most abundant were NKG2D+ cells, much more common than NK CD56+ ones. It implied that NKG2D was also expressed on T cells. Prevalence of NKG2D+ cells correlated with high activity of liver enzymes such as alanine aminotransferase, aspartate aminotransferase and a greater histological severity of liver injury. NKG2D+ cells form the bulk of cells infiltrating HCV-infected human liver. Correlation of NKG2D+ cells with some laboratory parameters of patients suggests their role in hepatitis C pathogenesis.
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