title: Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection.
abstract: The reactivation of latent human cytomegalovirus (HCMV) infection after transplantation is associated with high morbidity and mortality. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, whose establishment and/or maintenance require expression of the viral transcript UL138. Using stable isotope labeling by amino acids in cell culture-based mass spectrometry, we found a dramatic UL138-mediated loss of cell surface multidrug resistance-associated protein-1 (MRP1) and the reduction of substrate export by this transporter. Latency-associated loss of MRP1 and accumulation of the cytotoxic drug vincristine, an MRP1 substrate, depleted virus from naturally latent CD14(+) and CD34(+) progenitors, all of which are in vivo sites of latency. The UL138-mediated loss of MRP1 provides a marker for detecting latent HCMV infection and a therapeutic target for eliminating latently infected cells before transplantation.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Weekes
authors.forename: Shireen Y L
authors.initials: SY
authors.lastname: Tan
authors.forename: Emma
authors.initials: E
authors.lastname: Poole
authors.forename: Suzanne
authors.initials: S
authors.lastname: Talbot
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.forename: Duncan L
authors.initials: DL
authors.lastname: Smith
authors.forename: Christina
authors.initials: C
authors.lastname: Montag
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: John H
authors.initials: JH
authors.lastname: Sinclair
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000821:virology*; D003713:Dendritic Cells / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D055017:Monocyte-Macrophage Precursor Cells / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism*; D017735:Virus Latency
chemical_list: D018952:Antigens, CD34; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine; D014764:Viral Proteins; C421109:multidrug resistance-associated protein 1