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We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL\/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (T<jats:sub>RM<\/jats:sub>). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-\u03b3, TNF-\u03b1, and IL-2, upon <jats:italic>ex vivo<\/jats:italic> antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 T<jats:sub>RM<\/jats:sub> cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-\u03b3 upon <jats:italic>ex vivo<\/jats:italic> antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011697","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T17:48:52Z","timestamp":1696873732000},"page":"e1011697","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus 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