“Non-Essential” Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review

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  Figure 1. Nuclear functions of non-essential HSV-1 proteins. HSV-1 encodes multiple proteins able to counteract antiviral host responses within the nucleus. (A): ICP0 functions as an E3 ligase ubiquitin ligase that degrades ND10 components that encapsulate the viral genome in the nucleus, including PML, Daxx, SP100, centromeric proteins, and others. The degradation of IFI16 involves multiple factors. These events facilitate initiation of viral gene transcription. (B): The viral protein ICP0 is also known to disrupt repressor complexes that silence the viral genome, as well as recruit factors to enable viral gene transcription. Altogether, ICP0 facilitates permissive histone modifications, while suppressing silencing modifications, to enable for viral gene expression. (C): The viral kinases US3 and UL13, with ICP22, are known to facilitate viral late gene expression, which occurs through the recruitment of host factors, such as Topoisomerase IIα and RNA polymerase II, to the sites of DNA replication in the nucleus. Together, these non-essential viral proteins are important for optimal expression of other viral genes and for viral DNA replication.

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  Figure 2. Cytoplasmic functions of some non-essential HSV-1 proteins. (A): ICP0 participates in two major functions in the cytoplasm. First, ICP0 degrades the TLR2 adaptors TIRAP and Mal, thus blocking NF-κB activity. ICP0 also binds to the endocytosis adaptor CIN85 and along with Cbl promotes internalization of the viral entry receptor Nectin-1. This is a mechanism to promote progeny virus spread to uninfected cells. (B): The tegument protein UL46 blocks STING and TBK1, which prevents stimulation of interferon-regulated genes. ICP34.5 and US11 are also involved in blocking TBK1, emphasizing the importance of blocking TBK1 activity during HSV-1 infection. (C): The autophagy pathway is blocked during HSV-1 infection through binding of ICP34.5 to Beclin-1, thus preventing maturation of the autophagophore to an autophagosome. ICP0 has also been found to cause downregulation of p62 and OPTN proteins during infection, which may also serve as another mechanism of blocking selective autophagy. It has also been found that the protein encoded by UL12.5 causes depletion of mtDNA during infection, which causes damage to mitochondria. (D): HSV-1 prevents host translational shutoff from occurring…

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  Figure 3. HSV-1 egress and relevant non-essential proteins. Essential proteins are not depicted. (A) UL31 and UL34 form the Nuclear Egress Complex (NEC), which drives the vesiculation of the inner nuclear membrane (INM) and primary envelopment of HSV-1 capsids. (B) Nuclear de-envelopment is mediated by UL51. Tegument and envelope proteins assemble in a complex network on membranes derived from the trans-Golgi network. (C) HSV-1 capsids undergo cytoplasmic envelopment in a process regulated by multiple non-essential proteins, which involves functional redundancy. After cytoplasmic envelopment, enveloped virions are sorted to the extracellular space, which requires gK. HSV-1 release from the cell membrane can be inhibited by tetherin, which is counteracted by gM. (D) Depending on cell type (e.g., polarized epithelial cells), enveloped virions can disseminate through cell-to-cell spread, in a process that requires UL7/UL51 for sorting of virions towards parts of the membrane that contain gE/gI. Virions may spread to adjacent cells by binding to gE/gI receptors in adjacent cells. However, such receptors are unknown.

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  Figure 4. HSV-1 ocular infection based on data in mouse models. (A) HSV-1 can infect the eye through the cornea, where it can establish a productive infection in the corneal epithelium. The virus can then spread through the innervating sensory neurons to the trigeminal ganglia (TG), moving retrograde along axons towards the neuronal bodies. VP26 mediates migration to the TG. gE/gI and UL24 are important for trafficking of the virion along the axons towards the neuronal bodies. UL39/UL40 and TK are required for replication in cells that do not actively divide, such as neurons. gE/gI affect both retrograde and anterograde movement of the virion. (B) HSV-1 infection of the cornea: The virus can infect the upper layer of polarized epithelial cells, which requires gC and gG. Dissemination of the ocular infection requires the function of gE and gK, and further spread of the virus towards the underlying stromal layers of the cornea requires the function of VP22. HSV-1 can infect corneal afferent neurons and then spread towards the TG utilizing gE/gI. (C) HSV-1 can establish an infection in the retinal neuronal cells and can then move retrograde towards the cornea or anterograde towards the…