Transcriptional Regulation of Latency-Associated Transcripts (LATs) of Herpes Simplex Viruses

Abstract

Herpes simplex viruses (HSVs) cause cold sores and genital herpes and can establish lifelong latent infection in neurons. An engineered oncolytic HSV (oHSV) has recently been approved to treat tumors in clinics. HSV latency-associated transcripts (LATs) are associated with the latent infection, but LAT transcriptional regulation was seldom reported. For a better treatment of HSV infection and tumors, here we sequenced the LAT encoding DNA and LAT transcription regulatory region of our recently isolated new strain HSV-1-LXMW and did comparative analysis of the sequences together with those of other four HSV-1 and two HSV-2 strains. Phylogenetic analysis of LATs revealed that HSV-1-LXMW is evolutionarily close to HSV-1-17 from MRC University, Glasgow, UK. For the first time, Using a weight matrix-based program Match and multi-sequences alignment of the 6 HSV strains, we identified HSV LAT transcription regulatory sequences that bind to 9 transcription factors: AP-1, C-REL, Comp1, E2F, Hairy, HFH-3, Kr, TCF11/MAFG, v-Myb. Interestingly, these transcription regulatory sequences and factors are either conserved or unique among LATs of HSV-1 and HSV-2, suggesting they are potentially functional. Furthermore, literature analysis found that the transcription factors v-myb and AP-1 family member JunD are functional in regulating HSV gene transcription, including LAT transcription. For the first time, we discovered seven novel transcription factors and their corresponding transcription regulatory sequences of HSV LATs. Based on our findings and other reports, we proposed potential mechanisms of the initiation and maintenance of HSV latent infection. Our findings may have significant implication in our understanding of HSV latency and engineering of better oncolytic HSVs.

Multifunctional Non-Coding RNAs Mediate Latent Infection and Recurrence of Herpes Simplex Viruses

“…(b) A sufficient amount of IE gene expression can produce a large amount of ICP0 protein. ICP0 activates the JNK signaling pathway, and then AP-1 is phosphorylated by JNK and traffics into the neural nucleus, where AP-1 binds to the transcription regulatory sequence of LAT and activates LAT transcription as we reported recently, 10 leading to latent infection of HSV. At the same time, LAT transcription sequence is complementary to the IE gene encoding ICP0, which continuously consumes ICP0, resulting in the corresponding decrease in IE gene expression.…”

“… 8 , 9 Engineered oHSVs have been reported in many clinical trials. 10 T-VEC is an engineered oHSV with deletion of the genes ICP34.5 and ICP47 and insertion of the gene encoding human GM-CSF. 11 In 2015, T-VEC was approved to treat the advanced melanoma in US.…”

Oncolytic Engineering of ICP34.5 and LAT of Herpes Simplex Virus Type 1

“…Humans infected with HSV-1 may produce a series of skin lesions and neurotoxicity. Subsequently, HSV-1 establishes latency infection in the nervous system [11]. HSV-1 can be latent for several years or even a lifetime [12].…”

“…Perng G et al [31] reported the deletion of HSV-1 LAT genes. The absence of LAT and ICP34.5 prevents the virus from latency and reactivation, which means there has a long-term safe margin after treatment [11]. Therefore, LAT and ICP34.5 engineering are essential for the construction of oHSV.…”

The Role of VP16 in the Life Cycle of Alphaherpesviruses

“…Under the periodic stimulation of different stressors, the latent state of infected neurons is activated and then enters the lytic cycle to regenerate infectious virions (Kennedy et al, 2015;Whitley and Baines, 2018;Rübben, 2020). The establishment of latent infection is related to the interaction between the viral genome and the nuclear environment (Zhang et al, 2020). The viral genome and promyelocytic leukemia (PML) protein occupy the same nuclear region in infected neurons and eventually form nucleosome structures containing viral DNA (PML-NBs) (Cohen et al, 2018;Watson et al, 2018).…”