Immune Escape via a Transient Gene Expression Program Enables Productive Replication of a Latent Pathogen

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Jessica A. Linderman, Mariko Kobayashi, Vinayak Rayannavar, John J. Fak, Robert B. Darnell, Moses V. Chao, Angus C. Wilson, Ian Mohr
How type I and II interferons prevent periodic reemergence of latent pathogens in tissues of diverse cell types remains unknown. Using homogeneous neuron cultures latently infected with herpes simplex virus 1, we show that extrinsic type I or II interferon acts directly on neurons to induce unique gene expression signatures and inhibit the reactivation-specific burst of viral genome-wide transcription called phase I. Surprisingly, interferons suppressed reactivation only during a limited period early in phase I preceding productive virus growth. Sensitivity to type II interferon was selectively lost if viral ICP0, which normally accumulates later in phase I, was expressed before reactivation. Thus, interferons suppress reactivation by preventing initial expression of latent genomes but are ineffective once phase I viral proteins accumulate, limiting interferon action. This demonstrates that inducible reactivation from latency is only transiently sensitive to interferon. Moreover, it illustrates how latent pathogens escape host immune control to periodically replicate by rapidly deploying an interferon-resistant state.

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Teaser

How and where interferons suppress latent HSV-1 reactivation is poorly understood. Linderman et al. show that a neuron-intrinsic interferon response blocks reactivation by preventing the initial viral genome-wide burst of transcription. Furthermore, they establish that expressing HSV-1 ICP0 in this first phase temporally restricts IFN action to allow subsequent lytic replication.


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