KSHV infects B lymphocytes and establishes a predominantly latent infection. The detailed process and the mechanism underlying the establishment of latent infection remain elusive. After a KSHV particle enters a host cell, the virus undergoes DNA replication which results in accumulation of the viral genome to 50-100 copies per cell prior to establishment of latency. Little is known regarding the mode of the abortive viral replication and the regulation mechanism. ORF KS encodes a nuclear protein of the bZip family. Our study using K8-null recombinant virus demonstrated a role of KS in initial viral DNA replication following de novo KSHV Infection. KS-null viruses exhibit much lower viral genome copy numbers in comparison to wild type viruses when infecting 293T, HFF and HMVEC cells. The role of K8 in the early stage of de novo infection provides insights into the so-called "abortive viral replication". In this study, we will follow the functional role of K8 in the early stage of de novo infection to investigate the process of abortive viral replication that leads to establishment of latency and the mechanism controlling this process. In particular, (1) we will explore the role of K8 in the early stage of KSHV primary infection. We will test three non-exclusive models for the role of KB in this event: (i) K8 releases LANA-mediated ori-|yt-dependent viral DNA replication;(ii) K8 recruits the proteins required for abortive lytic DNA replication, viral or cellular inclusive of viral DMA polymerase;(iii) K8 represses some genes and activates other genes through epigenetic regulation of KSHV genome to facilitate effective abortive viral replication. (2) We will study the nature of abortive lytic replication in the early stage of KSHV primary infection. This may represent the third mode of viral DNA replication. We will study this crucial event by addressing the following questions: (i) Is the KSHV ori-Lyt involved in the abortive DNA replication? (ii) What mode of DNA replication is employed in the abortive lytic replication (3)? We will infect human PBMC with KSHV and analyze the contributions of K8 and other viral factors to the abortive replication that leads to establishment of latency in B cells. This study may leads to new strategy to interfere with KSHV life cycle aiming at efficacious treatment of KSHV-associated diseases.
Viral replication following de novo infection leads to an increase in viral genome number and is important for establishment of KSHV latency. This proposal will investigate this less explored event during the early stages of KSHV infection. The results of the study would provide an insight into the mechanism of this mode of replication which will leads to new strategies and therapies against KSHV-mediated diseases.
|Shukla, Sanket Kumar; Jha, Hem Chandra; El-Naccache, Darine W et al. (2016) An EBV recombinant deleted for residues 130-159 in EBNA3C can deregulate p53/Mdm2 and Cyclin D1/CDK6 which results in apoptosis and reduced cell proliferation. Oncotarget 7:18116-34|
|Jha, Hem Chandra; Banerjee, Shuvomoy; Robertson, Erle S (2016) The Role of Gammaherpesviruses in Cancer Pathogenesis. Pathogens 5:|
|Sun, Zhiguo; Jha, Hem Chandra; Pei, Yong-Gang et al. (2016) Major Histocompatibility Complex Class II HLA-DRÎ± Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8. J Virol 90:8047-58|
|Lieberman, Paul M (2016) Epigenetics and Genetics of Viral Latency. Cell Host Microbe 19:619-28|
|Jha, Hem C; Pei, Yonggang; Robertson, Erle S (2016) Epstein-Barr Virus: Diseases Linked to Infection and Transformation. Front Microbiol 7:1602|
|Huang, Hongda; Deng, Zhong; Vladimirova, Olga et al. (2016) Structural basis underlying viral hijacking of a histone chaperone complex. Nat Commun 7:12707|
|Gandhi, Jaya; Gaur, Nivedita; Khera, Lohit et al. (2015) COX-2 induces lytic reactivation of EBV through PGE2 by modulating the EP receptor signaling pathway. Virology 484:1-14|
|Uppal, Timsy; Jha, Hem C; Verma, Subhash C et al. (2015) Chromatinization of the KSHV Genome During the KSHV Life Cycle. Cancers (Basel) 7:112-42|
|Jha, Hem C; Yang, Karren; El-Naccache, Darine W et al. (2015) EBNA3C regulates p53 through induction of Aurora kinase B. Oncotarget 6:5788-803|
|Tsai, Kevin; Messick, Troy E; Lieberman, Paul M (2015) Disruption of host antiviral resistances by gammaherpesvirus tegument proteins with homology to the FGARAT purine biosynthesis enzyme. Curr Opin Virol 14:30-40|
Showing the most recent 10 out of 30 publications