Mathematical analysis demonstrates that interferons-beta and -gamma interact in a multiplicative manner to disrupt...

Several studies suggest that the innate interferons (IFNs), IFN-alpha and IFN-beta, can act in concert with IFN-gamma 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-alpha/beta and IFN-gamma 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-beta or IFN-gamma on HSV-1 replication over a 320,000-fold range of IFN concentration. Second, pharmacological methods prove that IFN-beta and IFN-gamma interact in a greater-than-additive manner to inhibit HSV-1 replication. Finally, the potency with which combinations of IFN-beta and IFN-gamma inhibit HSV-1 replication is accurately predicted by multiplying the individual inhibitory effects of each cytokine. Thus, IFN-beta and IFN-gamma interact in a multiplicative manner. We infer that a primary antiviral function of IFN-gamma lies in its capacity to multiply the potency with which IFN-alpha/beta restricts HSV-1 replication in vivo. This hypothesis has important ramifications for understanding how T lymphocyte-secreted cytokines such as IFN-gamma 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.