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. Furthermore, co-occurring mutations outside the epitope regions targeted by the immune response may increase or decrease the likelihood of survival of the variant (known as epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Here, using a rare cohort of subjects very recently infected with HCV, we build upon our prior investigations by integrating mathematical modelling and experimental data to examine the interplay between the evolving transmitted/founder (T/F) viruses, the adaptive immune response, viral fitness, and co-occurring mutations. We show that viral fitness decreases during the first 90 days post-infection (DPI) associated with the magnitude of CD8+ T-cell responses and the initial level of diversification. Thereafter, viral fitness rebounds in a complex pattern of evolution characterized by multiple sets of co-occurring mutations. Finally, we show that an early and strong CD8+ T-cell response in the absence of neutralizing antibodies (nAbs) imposes a strong selective force on the T/F virus population, enabling the virus to escape and establish chronic infection. Understanding these dynamics is highly relevant for HCV vaccine design and supports a vaccine strategy that induces broad immunity targeting both T and B cell responses.