Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Virus-Cell Interactions II Abstract 58<br />
CHARACTERISATION OF ENDOPLASMIC RETICULUM (ER) STRESS INDUCERS<br />
THAT LEAD TO KSHV REACTIVATION FROM LATENCY; IDENTIFYING<br />
PHYSIOLOGICAL TRIGGERS?<br />
Lucy Dalton-Griffin, Ed Tsao <strong>and</strong> Paul Kellam<br />
MRC centre for <strong>Medical</strong> Molecular virology, Department <strong>of</strong> Infection,<br />
<strong>University</strong> <strong>College</strong> London, 46 Clevel<strong>and</strong> Street, London, W1T 4JF, UK<br />
Abstract<br />
Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) like other herpesviruses has two stages<br />
to its life cycle; latency <strong>and</strong> lytic replication. KSHV is known to be required for<br />
development <strong>of</strong> Kaposi’s Sarcoma, a tumour <strong>of</strong> endothelial origin <strong>and</strong> is associated with<br />
the B-cell tumours, Primary Effusion Lymphomas (PELs) <strong>and</strong> the B-cell polyclonal<br />
expansion Multicentric Castleman’s Disease (MCD). Recently we <strong>and</strong> others have shown<br />
that the transcription factor X-box binding protein-1 (XBP-1) is a physiological trigger <strong>of</strong><br />
KSHV lytic reactivation in PEL. XBP-1 is responsible for the terminal differentiation <strong>of</strong> Bcells<br />
into plasma cells (PCs) as it is a major regulator <strong>of</strong> the unfolded protein response<br />
(UPR) <strong>and</strong> therefore allows production <strong>of</strong> large quantities <strong>of</strong> immunoglobulin in these<br />
cells. We have previously shown that PEL are blocked in differentiation by the absence <strong>of</strong><br />
active XBP-1; when provided the PEL cells differentiate towards a PC <strong>and</strong> induce KSHV<br />
lytic replication. Using an RFP lytic reactivation reporter assay we show that the ER stress<br />
inducer DTT activates the KSHV lytic cycle in an XBP-1 dependent manner. Recent<br />
studies have also indicated a role for hypoxia in reactivation via the hypoxia inducible<br />
factors (HIFs). Hypoxia can also result in XBP-1 activation as it is an ER stress inducer.<br />
Here we have investigated the roles <strong>of</strong> HIF-1α, HIF-2α <strong>and</strong> XBP-1 in activating the KSHV<br />
lytic cycle.<br />
Presenting author Email: ucbclda@ucl.ac.uk<br />
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