Virus-immune dynamics determined by prey-predator interaction network and epistasis in viral fitness landscape

Population dynamics and evolutionary genetics underly the structure of ecosystems, changing on the same timescale for interacting species with rapid turnover, such as virus (e.g. HIV) and immune response. Thus, an important problem in mathematical modeling is to connect ecology, evolution and genetics, which often have been treated separately. Here, extending analysis of multiple virus and immune response populations in a resource-prey (consumer)-predator model from Browne and Smith (2018), we show that long term dynamics of viral mutants evolving resistance at distinct epitopes (viral proteins targeted by immune responses) are governed by epistasis in the virus fitness landscape. In particular, the stability of persistent equilibrium virus-immune (prey-predator) network structures, such as nested and one-to-one, and bifurcations are determined by a collection of circuits defined by combinations of viral fitnesses that are minimally additive within a hypercube of binary sequences representing all possible viral epitope sequences ordered according to immunodominance hierarchy. Numerical solutions of our ordinary differential equation system, along with an extended stochastic version including random mutation, demonstrate how pairwise or multiplicative epistatic interactions shape viral evolution against concurrent immune responses and convergence to the multi-variant steady state predicted by theoretical results. Furthermore, simulations illustrate how periodic infusions of subdominant immune responses can induce a bifurcation in the persistent viral strains, offering superior host outcome over an alternative strategy of immunotherapy with strongest immune response.