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DAAs treatment achieved higher rates of sustained virological response among HCV-infected individuals across different virus genotypes. DAAs directly target HCV viral several proteins in the HCV lifecycle resulting in controlling the infection. So far, the immune system also plays a crucial role in effective viral eradication. Prolonged antigen exposure, coupled with high viral loads, are key factors that drive immune system failure and the development of chronic infection. T cell exhaustion is the hallmark of the failure of immune response to eliminate the infection. Several sequelae contribute to T cell exhaustion, including the failure of CD8+ and CD4+ T cells, the expansion of the immune suppressive effects of regulatory T cells, and the modulation of epigenetics, which collectively contribute to the persistence of HCV infection. The interplay between DAA therapy and the influence on immune response particularly T cell exhaustion is still an opening question. In this review, we shed light on the recent studies exploring the impact of DAA therapy on CD8+ and CD4+ T cell response as well as the epigenetics change. We also aim to bridge the gap in the new approaches to HCV control.<\/jats:p>","DOI":"10.1007\/s10238-025-01811-y","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T18:57:20Z","timestamp":1753901840000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unveiling the nexus between direct-acting antivirals in hepatitis C virus elimination and immune response"],"prefix":"10.1007","volume":"25","author":[{"given":"Aya I.","family":"Abdelaziz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Abdelsameea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara A.","family":"Wahdan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa","family":"Elsherbiny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeinab","family":"Zakaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0253-8280","authenticated-orcid":false,"given":"Samar S.","family":"Azab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"1811_CR1","doi-asserted-by":"crossref","first-page":"1041201","DOI":"10.3389\/fpubh.2023.1041201","volume":"11","author":"J Yang","year":"2023","unstructured":"Yang J, Qi JL, Wang XX, Li XH, Jin R, Liu BY, et al. 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