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viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism
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viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism
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viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism
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Journal Article
viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism
2015
Overview
Significance The entry of a virus into a cell is a fundamental step during infection. In certain herpesviruses, including Epstein–Barr virus, human herpesvirus 6, and human cytomegalovirus (HCMV), a viral glycoprotein complex, gH/gL, plays key roles in entry and is found in two different forms on virions. The relative abundance of the two different types of gH/gL complexes is influenced by the type of cell from which the virus is produced and influences the tropism of the virus for different cell types. We have identified a viral glycoprotein, UL148, that influences the cell tropism of HCMV virions by regulating the relative amounts of these two gH/gL complexes. Our findings have implications for understanding how herpesviruses navigate through host tissues.
Viral glycoproteins mediate entry of enveloped viruses into cells and thus play crucial roles in infection. In herpesviruses, a complex of two viral glycoproteins, gH and gL (gH/gL), regulates membrane fusion events and influences virion cell tropism. Human cytomegalovirus (HCMV) gH/gL can be incorporated into two different protein complexes: a glycoprotein O (gO)-containing complex known as gH/gL/gO, and a complex containing UL128, UL130, and UL131 known as gH/gL/UL128-131. Variability in the relative abundance of the complexes in the virion envelope correlates with differences in cell tropism exhibited between strains of HCMV. Nonetheless, the mechanisms underlying such variability have remained unclear. We have identified a viral protein encoded by the UL148 ORF ( UL148 ) that influences the ratio of gH/gL/gO to gH/gL/UL128-131 and the cell tropism of HCMV virions. A mutant disrupted for UL148 showed defects in gH/gL/gO maturation and enhanced infectivity for epithelial cells. Accordingly, reintroduction of UL148 into an HCMV strain that lacked the gene resulted in decreased levels of gH/gL/UL128-131 on virions and, correspondingly, decreased infectivity for epithelial cells. UL148 localized to the endoplasmic reticulum, but not to the cytoplasmic sites of virion envelopment. Coimmunoprecipitation results indicated that gH, gL, UL130, and UL131 associate with UL148, but that gO and UL128 do not. Taken together, the findings suggest that UL148 modulates HCMV tropism by regulating the composition of alternative gH/gL complexes.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Cells
/ Chromosomes, Artificial, Bacterial
/ Cytomegalovirus - metabolism
/ Cytomegalovirus - physiology
/ Endoplasmic Reticulum - metabolism
/ Epithelial Cells - metabolism
/ Glycoside Hydrolases - metabolism
/ Humans
/ Membrane Glycoproteins - metabolism
/ Mutation
/ tissues
/ Viral Envelope Proteins - genetics
/ Viral Fusion Proteins - genetics
/ Viral Fusion Proteins - metabolism
/ virion
/ viruses
