Abstract
Kaposi’s sarcoma associated herpesvirus (KSHV), like all herpesviruses maintains lifelong persistence with its host genome in latently infected cells with only a small fraction of cells showing signatures of productive lytic replication. Modulation of cellular signaling pathways by KSHV-encoded latent antigens, and microRNAs, as well as some level of spontaneous reactivation are important requirements for establishment of viral-associated diseases. Hypoxia, a prominent characteristic of the microenvironment of cancers, can exert specific effects on cell cycle control, and DNA replication through HIF1α-dependent pathways. Furthermore, hypoxia can induce lytic replication of KSHV. The mechanism by which KSHV-encoded RNAs and antigens regulate cellular and viral replication in the hypoxic microenvironment has yet to be fully elucidated. We investigated replication-associated events in the isogenic background of KSHV positive and negative cells grown under normoxic or hypoxic conditions and discovered an indispensable role of KSHV for sustained cellular and viral replication, through protection of critical components of the replication machinery from degradation at different stages of the process. These include proteins involved in origin recognition, pre-initiation, initiation and elongation of replicating genomes. Our results demonstrate that KSHV-encoded LANA inhibits hypoxia-mediated degradation of these proteins to sustain continued replication of both host and KSHV DNA. The present study provides a new dimension to our understanding of the role of KSHV in survival and growth of viral infected cells growing under hypoxic conditions and suggests potential new strategies for targeted treatment of KSHV-associated cancer.
Highlights
Kaposi Sarcoma associated herpesvirus (KSHV) or Human herpesvirus 8 (HHV8) infects human endothelial cells and B-lymphocytes and is strongly associated with Kaposi sarcoma (KS), Pleural Effusion Lymphoma (PEL) and Multicentric Castleman’s Disease (MCD) [1,2,3,4]
The two cells lines were checked for their isogenic background by short tandem repeat (STR) profiling and after thawing a similar passage number of cells was used for the experiment [26]
Cell cycle analysis of BJAB and BJAB-KSHV cells grown in hypoxia for different time periods clearly indicated that the presence of KSHV can facilitate the G1/S transition under hypoxic conditions (Fig 1B and 1C and S1 Fig)
Summary
Kaposi Sarcoma associated herpesvirus (KSHV) or Human herpesvirus 8 (HHV8) infects human endothelial cells and B-lymphocytes and is strongly associated with Kaposi sarcoma (KS), Pleural Effusion Lymphoma (PEL) and Multicentric Castleman’s Disease (MCD) [1,2,3,4]. KSHV maintains the viral genome as extra-chromosomal episomes in latently infected cells with only a limited number of KSHV-encoded genes expressed [5,6,7]. KSHV-encoded latency associated nuclear antigen (LANA) is the major factor responsible for maintaining latency as well as tethering the viral episomal DNA to host chromatin [5, 13,14,15]. Epigenetic reprogramming of the KSHV genome is another key requirement for maintaining latent infection and escaping from host immune response by switching off expression of the majority of the genes [19, 20]. The KSHV genome replicates once per cell cycle to maintain the gross copy number, and its replication is dependent on the host cellular machinery. Expression of Cdt, rescued the replication ability of plasmids containing the KSHV minimal replicator element [17]
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