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.
|Pandey, Saurabh; Robertson, Erle S (2018) Oncogenic Epstein-Barr virus recruits Nm23-H1 to regulate chromatin modifiers. Lab Invest 98:258-268|
|Liu, Dongcheng; Wang, Yan; Yuan, Yan (2018) Kaposi's Sarcoma-Associated Herpesvirus K8 Is an RNA Binding Protein That Regulates Viral DNA Replication in Coordination with a Noncoding RNA. J Virol :|
|Pandey, Saurabh; Jha, Hem Chandra; Shukla, Sanket Kumar et al. (2018) Epigenetic Regulation of Tumor Suppressors by Helicobacter pylori Enhances EBV-Induced Proliferation of Gastric Epithelial Cells. MBio 9:|
|Lang, Fengchao; Sun, Zhiguo; Pei, Yonggang et al. (2018) Shugoshin 1 is dislocated by KSHV-encoded LANA inducing aneuploidy. PLoS Pathog 14:e1007253|
|Pei, Yonggang; Singh, Rajnish Kumar; Shukla, Sanket Kumar et al. (2018) Epstein-Barr Virus Nuclear Antigen 3C Facilitates Cell Proliferation by Regulating Cyclin D2. J Virol 92:|
|Tso, For Yue; Kossenkov, Andrew V; Lidenge, Salum J et al. (2018) RNA-Seq of Kaposi's sarcoma reveals alterations in glucose and lipid metabolism. PLoS Pathog 14:e1006844|
|Mawhinney, Matthew T; Liu, Runcong; Lu, Fang et al. (2018) CTCF-Induced Circular DNA Complexes Observed by Atomic Force Microscopy. J Mol Biol 430:759-776|
|Li, Yuqing; Zhong, Canrong; Liu, Dawei et al. (2018) Evidence for Kaposi Sarcoma Originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition. Cancer Res 78:230-245|
|Pei, Yonggang; Lewis, Alexandria E; Robertson, Erle S (2017) Current Progress in EBV-Associated B-Cell Lymphomas. Adv Exp Med Biol 1018:57-74|
|Aneja, Kawalpreet K; Yuan, Yan (2017) Reactivation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus: An Update. Front Microbiol 8:613|
Showing the most recent 10 out of 48 publications