The interplay between human herpes simplex virus infection and the apoptosis and necroptosis cell death pathways

AbstractHuman herpes simplex virus (HSV) is a ubiquitous human pathogen that establishes a lifelong latent infection andis associated with mucocutaneous lesions. In multicellular organisms, cell death is a crucial host defense mechanismthat eliminates pathogen-infected cells. Apoptosis is a well-defined form of programmed cell death executed by agroup of cysteine proteases, called caspases. Studies have shown that HSV has evolved strategies to counteractcaspase activation and apoptosis by encoding anti-apoptotic viral proteins such as gD, gJ, Us3, LAT, and theribonucleotide reductase large subunit (R1). Recently, necroptosis has been identified as a regulated form ofnecrosis that can be invoked in the absence of caspase activity. Receptor-interacting kinase 3 (RIP3 or RIPK3) hasemerged as a central signaling molecule in necroptosis; it is activated via interaction with other RIP homotypicinteraction motif (RHIM)-containing proteins such as RIP1 (or RIPK1). There is increasing evidence that HSV R1manipulates necroptosis via the RHIM-dependent inactivation or activation ofRIP3 in a species-specific manner. Thisreview summarizes the current understanding of the interplay between HSV infection and cell death pathways,with an emphasis on apoptosis and necroptosis