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

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.Hepatitis C virus (HCV) causes chronic infection in  ～ 70% of infected people, who become at risk for developing severe liver diseases (1). The virus establishes chronic infection by using several molecular mechanisms for averting innate immunity and attenuating effectiveness of adaptive immune responses (2). HCV is one of the most heterogeneous viruses infecting humans and exists in each infected host as a population of genetically related variants (3, 4). Substantial heterogeneity and drastic changes in genetic composition of the intrahost HCV population observed during chronic infections have been interpreted as evidence of a continuous immune escape via random mutations, thereby generating increasing genetic diversity of viral populations in infected individuals (5–7).The observed cross-immunoreactivity (CR) of HCV variants from earlier stages of infection with antibodies (Abs) from later stages and ineffectiveness of Abs to immunoreact with variants from the same stage of infection (7) seemingly support the hypothesis of immune escape as a mechanism of intrahost evolution that contributes to establishment of persistent infections. However, several recent observations are incompatible with this hypothesis. First, the intrahost HIV population diversifies and diverts continuously from acute state to chronic infection until, at the onset of immunodeficiency, it starts losing heterogeneity and eventually stops diverting (8). Surprisingly, a similar temporal pattern of diversity and diversion was observed for intrahost HCV populations (9, 10). Furthermore, for HCV, the consistent increase in negative selection during chronic infection was observed (9–13). The late-stage HCV populations were shown to remain constant and homogeneous under the strong negative selection for years, indicating a high level of intrahost adaptation (9). Certain intrahost HCV variants were observed to persist in infected hosts for up to 16 y (9, 14, 15). These observations suggest that intrahost HCV subpopulations can remain unaffected by the immune system for years over the course of infection.Second, complex dynamics of HCV populations were observed in infected hosts. The density of intrahost subpopulations was found to fluctuate significantly in the course of chronic HCV infection, with some subpopulations persisting at low frequency for years until becoming dominant or reemerging at later stages of infection after being undetectable for a long time (9, 10, 15, 16).Third, the HCV hypervariable region 1 (HVR1) contains neutralizing antigenic epitopes (17, 18). Significant genetic variation of HVR1 during chronic infection was hypothesized to facilitate escape from neutralizing antibodies (17, 18). However, recent genetic and immunological analyses showed that HVR1 antigenic diversity is extensively convergent and effectively limited, with HVR1 variants from different genotypes and subtypes being broadly cross-immunoreactive (19–21).Interactions of intrahost viral variants with the host immune system are highly complex and nonlinear (22) and were subjects of mathematical modeling with the goal to understanding the mechanisms that lead to chronic infection. Previously developed mathematical models of interaction between HIV (23–25) or HCV (22) and the immune system showed that immune escape is associated with increase in diversity of the viral population. However, the continuous immune escape predicted by these models is inconsistent with the aforementioned observations, particularly for HCV. Unlike HIV, HCV lacks the ability to induce systemic immune suppression, suggesting a different mechanism of immune adaptation. Here, we develop a model that takes into consideration broad CR among viral variants (18, 19, 26–28) and disparity between CR and neutralization (19, 29). The model predicts antigenic cooperation (AC) among HCV variants that results in protection rather than continuous escape of the HCV population from the neutralizing Ab, thus suggesting a mechanism of intrahost evolution that leads to chronic infection.