Cellular sensing of viral DNA and viral evasion mechanisms

Abstract

Mammalian cells detect foreign DNA introduced as free DNA or as a result of microbial infection, leading to the induction of innate immune responses that block microbial replication and the activation of mechanisms that epigenetically silence the genes encoded by the foreign DNA. A number of DNA sensors localized to a variety of sites within the cell have been identified, and this review focuses on the mechanisms that detect viral DNA and how the resulting responses affect viral infections. Viruses have evolved mechanisms that inhibit these host sensors and signaling pathways, and the study of these antagonistic viral strategies has provided insight into the mechanisms of these host responses. The field of cellular sensing of foreign DNA is in its infancy, but our currently limited knowledge has raised a number of important questions for study.

Keywords: DNA sensors; IFI16; cGAS; epigenetics; herpes simplex virus; human immunodeficiency virus; innate responses; intrinsic resistance; vaccinia virus.

Figure 1

Models of viral DNA sensing. (a) Herpesviruses: Upon entry into cells, viral DNA is released into either the nucleus (fibroblasts) or cytosol (macrophages). IFI16 or cGAS senses the viral DNA and activates downstream signaling pathways. (b) HIV: Upon entry into the cytoplasm, viral RNA undergoes reverse transcription to produce single-stranded DNA (ssDNA) intermediates or final double-stranded DNA (dsDNA) molecules that are sensed by cytosolic sensors. Viral DNA enters the nucleus and integrates into cellular chromatin. (c) Poxviruses: Release of viral DNA into the cytosol activates DNA-PK and/or cGAS-dependent signaling. Other abbreviations: IFI16, interferon-inducible protein 16; cGAMP, cyclic GAMP; cGAS, cyclic GAMP synthase; DNA-PK, DNA-dependent protein kinase; STING, stimulator of interferon genes. Dashed arrows depict an undefined mechanism or a process that has not been examined.