Inhibition of superinfection and the evolution of viral latency

Abstract

Latent viruses generally defend their host cell against superinfection by nonlatent virulent mutants that could destroy the host cell. Superinfection inhibition thus seems to be a prerequisite for the maintenance of viral latency. Yet viral latency can break down when resistance to superinfection inhibition, known as ultravirulence, occurs. To understand the evolution of viral latency, we have developed a model that analyzes the epidemiology of latent infection in the face of ultravirulence. We show that latency can be maintained when superinfection inhibition and resistance against it coevolve in an arms race, which can result in large fluctuations in virulence. An example is the coevolution of the virulence and superinfection repressor protein of phage lambda (cI) and its binding target, the lambda oLoR operator. We show that this repressor/operator coevolution is the driving force for the evolution of superinfection immunity groups. Beyond latent phages, we predict analogous dynamics for any latent virus that uses a single repressor for the simultaneous control of virulence and superinfection.

FIG. 1.

Superinfection inhibition and its avoidance by ultravirulence (the example of phage λ). (A) Binding of the virulence repressor (R1) to the replication operator (O1) prevents replication of the resident and the superinfecting virus, and latency is maintained. (B) An ultravirulent operator mutant (O2) avoids repression by the resident wild-type repressor (R1) and will replicate and destroy the latently infected cell.

FIG. 2.

Ultravirulent operator mutants drive repressor evolution and create immunity groups. An ultravirulent operator mutant (R1O2) can superinfect and replace the wild type (R1O1). In turn, repressor mutants that compensate virulence (R2O2) are resistant to the ultravirulent-strain (R1O2) and invade. This process creates the two immunity groups R1O1 and R2O2. Now the operator O2 of immunity group R2O2 can either revert to R2O1 (which is ultravirulent with respect to R1O1) or form new operator alleles (e.g., O3). Resistance to the new operator allele O3 can be achieved by mutation to a matching repressor, R3. Origin and compensation of new operator alleles ultimately generate the diversity of immunity groups.

FIG. 3.

Generation and maintenance of immunity groups. (A) Simulation for two immunity groups in the operator reversion scenario. Repeated invasions lead to cycling and coexistence between two immunity groups (R1O1 and R2O2) driven by the appearance of ultravirulent operator mutations (R1O2 and R2O1). Invasions of ultravirulent mutants are marked by a steep increase of free viral particles. (B) New operator mutations drive the repeated repressor compensation and invasion of immunity groups. This invasion phase is followed by a fluctuation phase, in which previous immunity groups reappear. Diversification of immunity groups leads to an overall increase in virulence and free viral particles. We simulated equations in the Appendix (see “Invasion condition”), extended for 2 and 4 immunity groups, using NDSolve in the Mathematica 7.0 software program. Mutations to new operator and repressor types occur at rate 10⁻⁹ h⁻¹. Simulation parameters: K = 10⁵ cells; r = ρ = 1.3 h⁻¹; m = 0.1 h⁻¹; m_v = 0.01 h⁻¹; α_ii = 0.01 h⁻¹; α_ij = 0.6 h⁻¹; φ_ii = 0.01; φ_ij = 0.6; b = 6·10⁻⁹ h⁻¹·virus⁻¹; b_A = 10⁻⁷ h⁻¹·cells⁻¹; B = 100 virus·cells⁻¹; initial condition I₁₁ = 1.