The host cell represents a hostile environment that viruses must counter in order to establish infection. Human cytomegalovirus (HCMV) is no different and encodes a multitude of functions aimed at disabling, re-directing or hijacking cellular functions to promulgate infection. However, during the very early stages of infection the virus relies on the outcome of interactions between virion components, cell surface receptors and host signalling pathways to promote an environment that supports infection. In the context of latent infection—where the virus establishes an infection in an absence of many gene products specific for lytic infection—these initial interactions are crucial events. In this review, we will discuss key host responses triggered by viral infection and how, in turn, the virus ameliorates the impact on the establishment of non-lytic infections of cells. We will focus on strategies to evade intrinsic antiviral and innate immune responses and consider their impact on viral infection. Finally, we will consider the hypothesis that the very early events upon viral infection are important for dictating the outcome of infection and consider the possibility that events that occur during entry into non-permissive cells are unique and thus contribute to the establishment of latency.

Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity.

Type I interferons (IFN) are potent inducers of an anti-viral state in response to infection and have been demonstrated to inhibit cytomegalovirus (CMV) replication both in vitro and in vivo. CMV, like all herpes viruses, has the capacity to establish lifelong infections of host through the establishment of latency. As the very early stages of viral entry can trigger IFN responses we investigated the impact of IFN on the establishment of latent human CMV (HCMV) in myeloid progenitor cells. Here we show that priming of myeloid THP1 cells with type I IFN prior to infection skews infection towards a more efficient establishment of latency. This is evidenced by detection of reduced lytic gene expression, increased latent gene expression, and increased levels of reactivation following differentiation. Blockade of IFN signalling with neutralising antibodies antagonised the latent phenotype suggesting that endogenous IFN production upon infection contributed to the effect observed. Intriguingly, whilst both IFNα2 and IFNβ can drive latent infection individually, their effects were dose-dependent and demonstrated a biphasic impact on the establishment of latency, with the highest doses of IFN preventing both lytic and latent infection. These data demonstrate that the HCMV derives an unexpected benefit from IFN production. They support a hypothesis that, although anti-viral in nature, concentration-specific effects of IFN may be evident in the cells which can modulate different outcomes post infection in persistent viruses such as HCMV. Future work is identifying the IFN concentration-specific effects responsible for a cellular environment that favours the establishment of latency.

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