Drawing on disorder: How viruses use histone mimicry to their advantage

Tarakhovsky, Alexander; Prinjha, Rab K.

The ability of viruses to install the viral infection state implies the existence of mechanisms that allow the virus to override the robustness of the differentiated cell state imposed by the gene regulatory network (Macarthur et al., 2009; Huang, 2010) . Viral infection may cause a destabilization of the high-dimensional gene regulatory network, thereby facilitating exit of the cell from the differentiated attractor and entry into a potentially new metastable attractor state that benefits infection ( Fig. 1 C) . To achieve this aim, viruses need to interfere with the gene regulatory networks at points that operate as network hubs, or at multiple points, thus generating multiple perturbations to the system. The attractor view of the virus-induced cell phenotype can help to explain how multiple and diverse virus-driven events can lead to a common outcome, characterized by reduced antiviral responses and a rewiring of biosynthetic pathways to favor viral replication. In support of this model, screens for genes that control influenza infection performed by different laboratories have suggested highly variable cellular approaches toward antiviral resistance, with an abundance of host factors shown to contribute to the outcome of influenza infection. Remarkably, out of 1,539 total hits obtained in five genetic screens, 1,417 were unique to individual screens, and no genes were common to all five (Mehle and Doudna, 2010) . Moreover, only four genes were common in genome-wide screens in human cells (Brass et al., 2009; Karlas et al., 2010; König et al., 2010) . The same degree of inconsistency has been observed in multiple screens for the HIV host factors, for which several explanations have been proposed, mostly based on technical nuances of the screens (Goff, 2008; Bushman et al., 2009; Mehle and Doudna, 2010) . In our view, it is conceivable that these variations reflect the fact that establishment of the viral infection state can follow different paths that involve different genes. One can speculate that individual effects of the virus on the host do not need to be particularly specific or severe, but that the multiplicity of effects contributes to the establishment of the infected cell state. Such a scenario is similar to the use of different genetic networks for the generation of macrophages from undifferentiated tumor HL60 cells in response to chemically distinct triggers, all of which drive cells to the same attractor state (Huang et al., 2005) . How can viruses, frequently carrying just a bundle of genes, establish the infected cell state?