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J Cancer 2020; 11(11):3387-3399. doi:10.7150/jca.40186 This issue Cite

Research Paper

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

Ying Zhang^1,2,3*, Qiang Xin^4*, Jun-Yi Zhang^5*, Ying-Ying Wang^1,2,3, Jun-Ting Cheng^1,2,3, Wen-Qi Cai^1,2,3, Zi-Wen Han^1,2,3, Yang Zhou^1,2,3, Shu-Zhong Cui⁶, Xiao-Chun Peng^1,2,7, Xian-Wang Wang^1,2,8, Zhaowu Ma^1,2,3, Ying Xiang^1,2,3✉, Xiu-Lan Su^4✉, Hong-Wu Xin^1,2,3✉

1. The First School of Clinical Medicine, Health Science Center, Yangtze University, Nanhuan Road, Jingzhou, Hubei 434023, China.
2. Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei 434023, China
3. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.
4. Clinical Medical Research Center, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China.
5. Department of Neural Surgery, People's Hospital of Dongsheng District of Erdos City, Erdos, Inner Mongolia, 017000, China.
6. State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital Institute of Guangzhou Medical University, Guangzhou 510095, China.
7. Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.
8. Department of Laboratory Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei 434023, China.
*Authors contributed equally

✉ Corresponding authors: Ying Xiang, PhD, MD, Center for Molecular Medicine, School of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei 434023, China. Phone: +86 15107212530; Fax: 0716-8062633; Email: xying316com. Xiu-Lan Su, MD, Professor and Director, Clinical Medical Research Center, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China. Phone: 13904710692; Email: xlsucom. Hong-Wu Xin, PhD, MD, Professor and Chief, Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei 434023, China. Phone: +86 13311055391; Fax: 0716-8062633; Email: hongwu_xincom. More

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.

Keywords: oncolytic Herpes Simplex Virus (oHSV), Latency-Associated Transcripts (LATs), transcription regulatory regions (TRRs), Transcription Regulatory Sequences (TRSs), Transcription Factors (TFs), latent neural infection

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