Lorena Paule, Elisa Castillo, Leticia Muñoz, Javier Martínez, Carlos Fernández, Alejandro Miranda, Margaret Lario, Jorge Monserrat, Miguel Ángel Ortega, José Luis Calleja, Melchor Álvarez-Mon, Agustín Albillos
HCV infection was associated with marked Tc lymphopenia and selective depletion of naïve Th lymphocytes, regardless of fibrosis stage. These alterations were exacerbated in cirrhosis, particularly in decompensated disease, and closely resembled those observed in AL-cirrhosis. After SVR, HCV-NoF patients showed normalization of Tc counts, redistribution of Tc subsets, and restoration of Th1/Th17 balance and IFNγ/IL-17 profiles. In contrast, HCV-cirrhosis patients exhibited minimal immune recovery, with persistent Th and Tc lymphopenia, sustained depletion of naïve and central memory T lymphocyte subsets, and ongoing inflammatory cytokine skewing. CD25high Treg frequencies increased after SVR in both HCV groups but remained below HC levels, with normalization of chemokine receptor expression occurring only in HCV-NoF patients.
BACKGROUND: Direct-acting antivirals (DAAs) achieve sustained virological response (SVR) in over 95% of patients with chronic hepatitis C virus (HCV) infection. Although viral eradication allows partial immune restoration, it remains unclear whether established cirrhosis limits recovery of the circulating T lymphocyte compartment after SVR.
METHODS: We performed a phenotypic and functional analysis of circulating T-helper (Th) and T-cytotoxic (Tc) lymphocytes in patients with chronic HCV infection without fibrosis (HCV-NoF, n = 21) or with cirrhosis (HCV-cirrhosis, n = 20), as well as in alcohol-related cirrhosis (AL-cirrhosis, n = 12) and healthy controls (HC, n = 12). HCV patients were evaluated at baseline and 14 weeks after SVR following DAA therapy. Peripheral blood mononuclear cells were analysed by flow cytometry to quantify T lymphocyte subsets, cytokine production (IFNγ, IL-17), and regulatory T lymphocytes (CD25high Tregs).
RESULTS: HCV infection was associated with marked Tc lymphopenia and selective depletion of naïve Th lymphocytes, regardless of fibrosis stage. These alterations were exacerbated in cirrhosis, particularly in decompensated disease, and closely resembled those observed in AL-cirrhosis. After SVR, HCV-NoF patients showed normalization of Tc counts, redistribution of Tc subsets, and restoration of Th1/Th17 balance and IFNγ/IL-17 profiles. In contrast, HCV-cirrhosis patients exhibited minimal immune recovery, with persistent Th and Tc lymphopenia, sustained depletion of naïve and central memory T lymphocyte subsets, and ongoing inflammatory cytokine skewing. CD25high Treg frequencies increased after SVR in both HCV groups but remained below HC levels, with normalization of chemokine receptor expression occurring only in HCV-NoF patients.
DISCUSSION: Cirrhosis profoundly constrains immune reconstitution after HCV cure, limiting post-treatment T-cell recovery.