A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery

Abstract

During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies.

Modulation of mRNA 3′-End Processing and Transcription Termination in Virus-Infected Cells

“…Thus, viruses can co-opt host transcriptional and translational machinery for viral gene expression, as well as reduce expression of host genes that may be detrimental to viral survival and proliferation (26,27). Diverse mechanisms underlie these effects on host cells, including suppression of transcription through interaction of viral proteins with transcription factors and promoters, inhibition of Pol II elongation, and degradation of Pol II through ubiquitination (28)(29)(30)(31). Viral infection also interferes with mRNA processing and stability through its effects on splicing, 5´capping, and nuclear export of cellular mRNAs as well as induction of mRNA degradation (32)(33)(34)(35)(36)(37).…”

“…Infection with herpes simplex virus-1 (HSV-1) causes disruption of transcription termination in host genes via its immediate-early protein ICP27 ( 31 , 47 , 48 ). Deletion of ICP27 significantly reduces disruption of host termination, and ectopic expression of the protein is sufficient to inhibit RNA Pol II termination ( 48 ).…”

“…RdRP elongates the viral mRNA using the viral RNA (vRNA) as a template until it reaches a 5´-U track in the vRNA, which serves as a signal and template for polyadenylation by RdRP, avoiding the use of host transcription and 3´-end processing machinery altogether ( Figure 2A ) ( 32 , 61 , 62 ). In contrast, HSV-1 is a double-stranded DNA virus that relies on the host transcription machinery and 3´-end processing complex ( 28 , 31 ). Intriguingly, HSV-1 protein ICP27, while globally disrupting transcription termination, conversely facilitates RNA processing of HSV-1 mRNAs ( 48 ).…”

“…Regardless of the cause, it is now evident that read-through transcripts are often not polyadenylated, are retained in the nucleus, and thus are non-coding ( 40 , 47 , 66 ). Notably, the fraction of transcripts that are read through from a given gene is significantly greater in virus-infected than in stressed cells, perhaps explaining why readthrough is strongly associated with reduced expression of the read-through gene during viral infection ( 31 , 60 ). A similar response has not been clearly demonstrated in stressed cells ( 60 ).…”

“…Aberrant intergenic splicing was more prevalent in HSV-1-infected cells compared to cells experiencing hyperosmotic stress ( 60 ). This finding can likely be attributed to the significantly higher extent of read-through transcription and the longer length of the read-through transcripts produced during HSV-1 infection than during cellular stress ( 31 ). Further work is needed to elucidate the relationship between read-through transcription and changes in splicing events.…”