## 7 HCV and Immune System  
The cellular innate immune response plays a pivotal role in the host defense against HCV infection, with natural killer (NK) cells being among the most crucial effectors of early antiviral immunity. NK cells constitute approximately 30-50% of the total lymphocyte population in the liver, underscoring their significant role in immunosurveillance and antiviral defense within this organ [51]. These cells are primarily classified based on the expression patterns of the surface markers CD16 and CD56, which influence their functional properties. NK cells expressing CD16 + CD56 dim are predominantly cytotoxic, exhibiting strong effector functions, including direct target cell lysis, whereas CD16 \(-\) CD56 bright NK cells exhibit a primarily immunoregulatory and cytokine-producing phenotype. Numerous studies have documented viral infections' influence on NK activity, which was also found to be affected in HCV patients. Specifically, infections caused by cytomegalovirus, Epstein-Barr virus, and herpes virus have been associated with a reduction in spontaneous NK cell cytotoxic activity. This observed decline in cytotoxic response may arise from either the \begin{table}
\begin{tabular}{l l l} \hline
**Study/Reference** & **Population** & **Key Findings** \\ \hline \multirow{6}{*}{[PERSON] et al., 2016 [39]} & & Significant reduction in gut microbiome diversity in HCV-infected patients. The potential alteration of the microbiome in chronic hepatitis C may be influenced by bacterial translocation, alongside the liver’s compromised functions in digestion and protein synthesis. \\ \cline{2-3}  & & Gut dysbiosis observed even in asymptomatic patients; progression of clinical stage associated with further dysbiosis. In individuals infected with HCV, there was a notable reduction in bacterial diversity when contrasted with healthy subjects. This decline was particularly evident in the Clostrtiales order, while an increase was observed in the populations of Streptococcus and Lactobacillus. \\ \hline \multirow{6}{*}{[PERSON] et al., 2022 [43]} & & Altered gut microbiome composition observed; specific bacterial taxa changes noted. The gut microbiota in patients infected with HCV exhibits alterations when compared to uninfected controls; however, the overall composition of the microbiome does not show significant changes in the short term following the eradication of HCV. \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \cline{1-1} \cline{2-3}  & & \\ \hline \end{tabular}
\end{table} 
Table 1: Summary of studies on HCV infection and gut microbiota alterations. direct infection of NK cells by the viruses or the release of soluble factors from infected cells that modulate the spontaneous cytotoxicity of NK cells [51]. One of the principal mechanisms through which NK cells contribute to the control of HCV infection is the secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-\(\alpha\)) and interferon-gamma (IFN-\(\gamma\)). These cytokines exert antiviral effects by suppressing HCV replication and modulating the broader immune response. Additionally, NK cells employ direct cytolytic mechanisms, including the release of perforin and granzyme, to induce apoptosis in infected hepatocytes. However, this cytotoxic response, while crucial for viral clearance, may also contribute to unintended liver injury by promoting tissue damage and inflammation [52]. During HCV infection, an upregulation of killer immunoglobulin-like receptors (KIRs) on NK cells has been observed, reflecting the critical role of these immune cells in mediating target cell lysis.