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PMID: 18684478 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Genetic disruption of KSHV major latent nuclear antigen LANA enhances viral lytic transcriptional program.

Virology ·Vol. 379 ·No. 2 ·2008-09-30 ·Pages 234-44

Li Q, Zhou F, Ye F, Gao SJ

Abstract

Following primary infection, KSHV establishes a lifelong persistent latent infection in the host. The mechanism of KSHV latency is not fully understood. The latent nuclear antigen (LANA or LNA) encoded by ORF73 is one of a few viral genes expressed during KSHV latency, and is consistently detected in all KSHV-related malignancies. LANA is essential for KSHV episome persistence, and regulates the expression of viral lytic genes through epigenetic silencing, and inhibition of the expression and transactivation function of the key KSHV lytic replication initiator RTA (ORF50). In this study, we used a genetic approach to examine the role of LANA in regulating KSHV lytic replication program. Deletion of LANA did not affect the expression of its adjacent genes vCyclin (ORF72) and vFLIP (ORF71). In contrast, the expression levels of viral lytic genes including immediate-early gene RTA, early genes MTA (ORF57), vIL-6 (ORF-K2) and ORF59, and late gene ORF-K8.1 were increased before and after viral lytic induction with 12-O-tetradecanoyl-phorbol-13-acetate and sodium butyrate. This enhanced expression of viral lytic genes was also observed following overexpression of RTA with or without simultaneous chemical induction. Consistent with these results, the LANA mutant cells produced more infectious virions than the wild-type virus cells did. Furthermore, genetic repair of the mutant virus reverted the phenotypes to those of wild-type virus. Together, these results have demonstrated that, in the context of viral genome, LANA contributes to KSHV latency by regulating the expression of RTA and its downstream genes.

MeSH Terms
Antigens, Viral/genetics,physiology Base Sequence Cell Line DNA Primers/genetics Gene Expression/drug effects Genes, Viral Herpesvirus 8, Human/genetics,immunology,pathogenicity,physiology Humans Nuclear Proteins/genetics,physiology RNA, Messenger/genetics,metabolism RNA, Viral/genetics,metabolism Sequence Deletion Tetradecanoylphorbol Acetate/pharmacology Transcription, Genetic Viral Proteins/genetics Virus Latency/genetics,immunology Virus Replication/genetics,immunology
Chemicals
Antigens, Viral DNA Primers Nuclear Proteins RNA, Messenger RNA, Viral Viral Proteins latency-associated nuclear antigen viral FLIP protein, Human herpesvirus 8 Tetradecanoylphorbol Acetate
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Li Qiuhua
Tumor Virology Program, Greehey Children's Cancer Research Institute, Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Drive, San Antonio, TX 78229, USA.
Zhou Fuchun
Ye Fengchun
Gao Shou-Jiang
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Article Info
Journal
Virology
Abbr.
Virology
ISSN
1096-0341
DOI
10.1016/j.virol.2008.06.043
Published
2008-09-30
Epub
2008-00-05
Pages
234-44
Language
English
Region
United States
NLM ID
0110674
PMCID
PMC2626151
Subset
IM
Grants
NCI NIH HHS · R01 CA124332-02S1 · United States
NCI NIH HHS · R01 CA096512 · United States
NIDCR NIH HHS · R01 DE017333-02 · United States
NCI NIH HHS · R01 CA096512-03 · United States
NCI NIH HHS · CA119889 · United States
NCI NIH HHS · R01 CA096512-05 · United States
NIDCR NIH HHS · DE017333 · United States
NCI NIH HHS · CA096512 · United States
NIDCR NIH HHS · R01 DE017333 · United States
NCI NIH HHS · R01 CA124332-01A2 · United States
NCI NIH HHS · R01 CA096512-04 · United States
NCI NIH HHS · R01 CA132637 · United States
NCI NIH HHS · R01 CA132637-01A1 · United States
NCI NIH HHS · R01 CA124332-02 · United States
NCRR NIH HHS · M01 RR001346 · United States
NCI NIH HHS · R01 CA124332 · United States
NCI NIH HHS · R01 CA096512-01A2 · United States
NCI NIH HHS · R01 CA096512-02 · United States
NCRR NIH HHS · M01 RR001346-258134 · United States
NCRR NIH HHS · M01 RR001346-266913 · United States
NCI NIH HHS · CA124332 · United States
NIDCR NIH HHS · R01 DE017333-01 · United States
NIDCR NIH HHS · R01 DE017333-03 · United States
External Links
PubMed source DOI: 10.1016/j.virol.2008.06.043 PMC Full Text
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