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.

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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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-2)
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University of Pennsylvania
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