Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Significance Immune escape by continuous genetic diversification is commonly described using a metaphor of “arms race” between virus and host. Here we show, however, that hepatitis C virus (HCV) genetic heterogeneity facilitates a stable state of immune adaptation rather than perpetuates an arms race. We developed a mathematical model that considers variation in breadth of immunoreactivity among antibodies and antigens and the contribution of immune memory to humoral response against HCV. The model applied to a complex network of cross-immunoreactivity suggests antigenic cooperation among variants as a mechanism of mitigating the immune pressure on certain HCV variants. Cooperative action of antigens results from their differential capability to bind or elicit highly polyspecific antibodies. Antigenic cooperation is a new target for therapeutic- and vaccine-development strategies. Hepatitis C virus (HCV) has the propensity to cause chronic infection. Continuous immune escape has been proposed as a mechanism of intrahost viral evolution contributing to HCV persistence. Although the pronounced genetic diversity of intrahost HCV populations supports this hypothesis, recent observations of long-term persistence of individual HCV variants, negative selection increase, and complex dynamics of viral subpopulations during infection as well as broad cross-immunoreactivity (CR) among variants are inconsistent with the immune-escape hypothesis. Here, we present a mathematical model of intrahost viral population dynamics under the condition of a complex CR network (CRN) of viral variants and examine the contribution of CR to establishing persistent HCV infection. The model suggests a mechanism of viral adaptation by antigenic cooperation (AC), with immune responses against one variant protecting other variants. AC reduces the capacity of the host’s immune system to neutralize certain viral variants. CRN structure determines specific roles for each viral variant in host adaptation, with variants eliciting broad-CR antibodies facilitating persistence of other variants immunoreacting with these antibodies. The proposed mechanism is supported by empirical observations of intrahost HCV evolution. Interference with AC is a potential strategy for interruption and prevention of chronic HCV infection.