Evasion of early antiviral responses by herpes simplex viruses

Abstract

Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency.

Figure 1

HSVs interfere with host detection of viral determinants. Immune and nonimmune cells express an array of pathogen recognition receptors intended to detect microbes, which ultimately lead to NF-κB and IRF translocation into the nucleus and secretion of antiviral molecules, such as interferons and cytokines. A: Host cells can sense HSV determinants through TLR2, although the specific viral elements detected by this receptor are currently unknown. Intracellular signaling through TLR2 can occur with the help of integrin ανβ3-binding after this receptor binds with the HSV complex gH/gL. B: Alternatively, integrin ανβ3 can signal intracellularly on its own after gH/gL binding. This process can be interfered by ICP0 C: TLR3, D: TLR7, and E: TLR9 engagement by activating ligands, such as polyI:C, imiquimod (IM), and CpG-ODN, respectively, have been shown to play favorable roles against HSV infection by inducing activating pathways within cells that lead to the secretion of antiviral molecules. F: Nucleic acids generated during HSV infection can also be detected by host intracellular sensors, such as DAI, cGAS, and IFI16. G: The RIG-1/MDA5 complex can also detect virus-derived nucleic acids; however its function is blocked by viral vhs. H: Finally, the inflammasome is activated by HSV determinants, although HSV ICP0 can counteract its activity and negatively modulate its function.

Figure 2

HSVs interfere with cell viability. HSVs encode determinants that modulate cell viability. (a) Within epithelial cells, HSV can extend the survival of cells by blocking apoptosis thanks to viral proteins, such as gD, gJ, UL14, ICP0, and US3. Tetherin, a host antiviral factor involved in blocking virus release from the surface of infected cells, is blocked by HSV vhs. Contrarily, fibroblasts display necrosis upon infection with HSV, which would be mediated by ICP6. (b) Dendritic cells display apoptosis early after infection with HSVs by unknown viral determinants. The autophagosome, which mediates virus control in these and other cells, such as neurons, is inhibited by the viral protein γ34.5. HSV also induces apoptosis of NK cells, albeit through Fas/FasL interactions between these cells and HSV-infected macrophages.

Figure 3

HSVs interfere with the induction of type-I interferons and interferon signaling. A: HSV vhs proteins interfere with cell protein translation by specifically degrading host mRNAs. B: Viral US11 and γ34.5 interfere with host PKR function, by impairing its capacity to phosphorylate EIF2A, which blocks translation within infected cells. C: Host sensors activate TRAF3 after detecting HSV determinants, which normally leads to IRF3 activation. However, UL36 interferes with TRAF3 ubiquitination blocking its IRF3-activating capacity. ICP0 and US3 also interfere with IRF3 activation. Impaired IRF3 function will result in poor secretion of interferons by infected cells. D: Viral ICP27 interferes with STAT-1 signaling mediated by IFNR, which would otherwise lead to the secretion of antiviral effectors.