Supervisor: Professor Paul Lehner
Following primary infection, human cytomegalovirus (HCMV) typically establishes a latent infection under the control of a healthy immune system. A key site of latency of HCMV is in cells of the myeloid lineage, where the viral genome persists within the latently infected cell with little gene expression and no detectable production of infectious virions. Reactivation from viral latency occurs when cellular conditions become permissive for lytic gene expression, such as when a latently infected undifferentiated myeloid cell differentiates into a mature dendritic cell. While HCMV typically causes few, if any, overt symptoms in immunocompetent individuals, reactivation or primary infection of HCMV causes serious disease in immunocompromised individuals.
UL138 is one of four known latency associated HCMV genes, and is also expressed during lytic-phase infection. We used a SILAC-based proteomics approach, ‘Plasma Membrane Profiling’, in the THP-1 monocytic leukaemia cell line to identify cell surface proteins whose expression is altered by UL138. We identified several proteins, including the plasma membrane transporter multidrug-resistance associated protein 1 (MRP1) that was downregulated in the presence of UL138. We have confirmed this downregulation in lytic infection and in experimental latency. As MRP1 is a drug transporter, we used a cytotoxic MRP1 substrate to target HCMV-infected cells in both experimental and natural latency, providing a therapeutic opportunity to purge HCMV-infected cells.
Weekes MP, Tan SYL, Poole E, Talbot S, Antrobus R, Smith DL, Montag C, Gygi SP, Sinclair JH, Lehner PJ. 2013. Latency-associated degradation of the MRP1 drug transporter during latent Human Cytomegalovirus infection. Science. 340:199-202.