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This definition can be divided into intrinsic fitness\u2014fitness without immune pressure\u2014and effective fitness, which includes immune influence. Co-occurring mutations outside immune-targeted epitope regions may also affect variant survival (epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Using a rare cohort of subjects recently infected with HCV, we build on prior work by integrating mathematical modeling and experimental data to examine the interplay between transmitted\/founder (T\/F) viruses, immune responses, fitness, and co-occurring mutations. We show that viral fitness declines during the first 90 days post-infection (DPI), associated with the magnitude of CD8 +T cell responses and early diversification. Fitness then rebounds in a complex pattern marked by co-occurring mutations. Finally, we demonstrate that an early, strong CD8 +T cell response in the absence of neutralizing antibodies (nAbs) exerts strong selective pressure, allowing escape and chronic infection. These insights support HCV vaccine strategies that elicit broad T and B cell immunity.<\/jats:p>","DOI":"10.7554\/elife.102232","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T11:28:33Z","timestamp":1731497313000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.102232","source":"Crossref","is-referenced-by-count":1,"title":["Temporal dynamics of viral fitness and the adaptive immune response in HCV infection"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9731-9880","authenticated-orcid":true,"given":"Melanie Rose","family":"Walker","sequence":"first","affiliation":[{"name":"Viral Immunology Systems Program, The Kirby Institute","place":["Sydney, Australia"]},{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, Faculty of Medicine, The University of New South Wales","place":["Sydney, 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