Halford William P, Halford Keith J, Pierce Amy T
Department of Microbiology and Immunology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
J Theor Biol. 2005 Jun 7;234(3):439-54. doi: 10.1016/j.jtbi.2004.12.007. Epub 2005 Jan 25.
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.
多项研究表明，先天性干扰素（IFN），即IFN-α和IFN-β，可与IFN-γ协同作用，以协同抑制巨细胞病毒和1型单纯疱疹病毒（HSV-1）的复制。这一观察结果的重要性在很大程度上尚未达成共识，因为IFN-α/β与IFN-γ之间相互作用的性质和程度尚未明确界定。在本研究中，我们通过证明三点来解决这个问题。第一，双曲正切函数tanh (x)可用于描述在320,000倍IFN浓度范围内IFN-β或IFN-γ对HSV-1复制的个体效应。第二，药理学方法证明IFN-β和IFN-γ以大于相加的方式相互作用以抑制HSV-1复制。最后，通过将每种细胞因子的个体抑制作用相乘，可以准确预测IFN-β和IFN-γ组合抑制HSV-1复制的效力。因此，IFN-β和IFN-γ以相乘方式相互作用。我们推断，IFN-γ的主要抗病毒功能在于其能够增强IFN-α/β在体内限制HSV-1复制的效力。这一假设对于理解T淋巴细胞分泌的细胞因子如IFN-γ如何能使疱疹病毒进入潜伏状态而不破坏在宿主一生中持续携带这些病毒感染的神经元或白细胞具有重要意义。
