Temporal dynamics of viral fitness and the adaptive immune response in HCV infection

Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. This definition can be divided into intrinsic fitness—fitness without immune pressure—and 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.