Mathematical analysis demonstrates that interferons-β and -γ Interact in a multiplicative manner to disrupt herpes simplex virus replication

Abstract

Several studies suggest that the innate interferons (IFNs), IFN- α and IFN- β , can act in concert with IFN- γ to synergistically inhibit the replication of cytomegalovirus and herpes simplex virus type 1 (HSV-1). The significance of this observation is not yet agreed upon in large part because the nature and magnitude of the interaction between IFN- α/β and IFN- γ is not well defined. In the current study, we resolve this issue by demonstrating three points. First, the hyperbolic tangent function, tanh ( x ), can be used to describe the individual effects of IFN- β or IFN- γ on HSV-1 replication over a 320,000-fold range of IFN concentration. Second, pharmacological methods prove that IFN- β and IFN- γ interact in a greater-than-additive manner to inhibit HSV-1 replication. Finally, the potency with which combinations of IFN- β and IFN- γ inhibit HSV-1 replication is accurately predicted by multiplying the individual inhibitory effects of each cytokine. Thus, IFN- β and IFN- γ interact in a multiplicative manner. We infer that a primary antiviral function of IFN- γ lies in its capacity to multiply the potency with which IFN- α/β restricts HSV-1 replication in vivo. This hypothesis has important ramifications for understanding how T lymphocyte-secreted cytokines such as IFN- γ can force herpesviruses into a latent state without destroying the neurons or leukocytes that continue to harbor these viral infections for the lifetime of the host.