HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

Ryckman, Brent J.; Chase, Marie C.; Johnson, David C.

doi:10.1073/pnas.0804365105

Cited by 151 publications

(174 citation statements)

References 45 publications

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“…Pentamer overexpression specifically inhibits HCMV infection of epithelial cells, but not fibroblasts, whereas overexpression of gH/gL/gO interferes with HCMV entry in fibroblasts, but not epithelial/endothelial cells (17,21). These data point to the existence of cell-specific entry receptors for gH/gL/gO and Pentamer, respectively.…”

Section: Discussionmentioning

confidence: 80%

“…To investigate the role of the disulfide bond between gL-Cys-144 and UL128-Cys-162 in HCMV infection we assessed the effect of the single and double Cys→Ser mutations in Pentamer-mediated interference of viral entry in adult retinal pigment epithelial 19 (ARPE-19) cells (17,21). Cells were transduced with adenoviruses (AdVs) expressing the full-length Pentamer proteins, followed by infection with HCMV (lowpassage HCMV clinical isolate VR1814).…”

Section: Effects Of Ul128-cys-162 And/or Gl-cys-144 Mutations On Pentmentioning

confidence: 99%

“…Cells were transduced with adenoviruses (AdVs) expressing the full-length Pentamer proteins, followed by infection with HCMV (lowpassage HCMV clinical isolate VR1814). In this assay, Pentamer can bind and sequester host molecules required for viral entry, thus protecting cells from HCMV infection (17). VR1814 has an accelerated viral gene expression profile compared with various other clinical isolates and laboratory strains tested (34).…”

Section: Effects Of Ul128-cys-162 And/or Gl-cys-144 Mutations On Pentmentioning

confidence: 99%

“…Mutations in the UL131A-UL128 gene locus are sufficient to eliminate epithelial/endothelial tropism and occur spontaneously within only a few passages of wild-type (WT) HCMV in fibroblasts (15,16). In addition, Pentamer cell surface overexpression interferes with HCMV entry into epithelial cells, but not into fibroblasts, suggesting the presence of a cell-typespecific Pentamer receptor (17).…”

mentioning

confidence: 99%

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Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Ciferri

Chandramouli

Donnarumma

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

141

189

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Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and the leading viral cause of birth defects after congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are key targets of the human humoral response against HCMV and are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively. We expressed and characterized soluble forms of gH/gL, gH/gL/gO, and Pentamer. Mass spectrometry and mutagenesis analysis revealed that gL-Cys144 forms disulfide bonds with gO-Cys351 in gH/gL/gO and with UL128-Cys162 in the Pentamer. Notably, Pentamer harboring the UL128-Cys162Ser/gL-Cys144Ser mutations had impaired syncytia formation and reduced interference of HCMV entry into epithelial cells. Electron microscopy analysis showed that HCMV gH/gL resembles HSV gH/gL and that gO and UL128/UL130/UL131A bind to the same site at the gH/gL N terminus. These data are consistent with gH/gL/gO and Pentamer forming mutually exclusive cell entry complexes and reveal the overall location of gH/gL-, gH/gL/ gO-, and Pentamer-specific neutralizing antibody binding sites. Our results provide, to our knowledge, the first structural view of gH/gL/ gO and Pentamer supporting the development of vaccines and antibody therapeutics against HCMV.human cytomegalovirus | HCMV | Pentamer complex | gH/gL/gO | virus entry

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Section: Discussionmentioning

confidence: 80%

Section: Effects Of Ul128-cys-162 And/or Gl-cys-144 Mutations On Pentmentioning

confidence: 99%

Section: Effects Of Ul128-cys-162 And/or Gl-cys-144 Mutations On Pentmentioning

confidence: 99%

mentioning

confidence: 99%

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Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Ciferri

Chandramouli

Donnarumma

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

141

189

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“…HCMV glycoprotein H (gH) and glycoprotein L (gL) gene products can be incorporated into two different protein complexes involved in CMV infectivity: 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. The UL131A-UL128 associates with gH and gL to produce a pentameric complex, gH/gL/UL131A-UL128, required for HCMV entry into ECs, epithelial cells, dendritic cells and macrophages (40)(41)(42)(43). In contrast, viral entry into fibroblasts have genetic determinants in complex gH/gL/gO (or gH/gL) in which HCMV glycoprotein gO coassociates with gH/gL and acts as a gH/gL chaperone (44).…”

Section: Variability Of CMV Strainsmentioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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Cytomegalovirus infection in pregnancy

Davis

King

Kourtis

2017

Birth Defects Research

119

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Cytomegalovirus (CMV) is a DNA herpesvirus that is common worldwide. The two known main sources of primary CMV infection during pregnancy are through sexual activity and contact with young children. Primary infection occurs in approximately 1 to 4% of pregnancies, and is mostly asymptomatic in immunocompetent adults. However, primary infection may manifest as a mild mononucleosis or flu-like syndrome with persistent fever and fatigue. CMV can be transmitted from mother-to-child in utero, intrapartum, or during breastfeeding. Intrauterine transmission can lead to congenital CMV infection, a leading cause of permanent hearing and vision loss and neurological disability among children. Congenital CMV transmission rates are as high as 50% in women who acquire primary CMV infection during pregnancy, and less than 2% in women with nonprimary infection. There is no licensed CMV vaccine. Good hygiene practices and avoiding intimate contact with young children (e.g., kissing on the mouth and sharing utensils) have been suggested as an approach to prevent maternal primary CMV infection during pregnancy, but remains an unproven method of reducing the risk of congenital CMV infection. Approximately 1 in 10 infants who acquire CMV in utero will have clinical signs at birth, and an additional 10 to 15% will go on to develop late-onset sequelae. Antiviral treatment prenatally and postnatally has not proven effective at preventing congenital or postnatal CMV infection, and is not recommended for routine clinical care. However, antiviral treatment when initiated in the first month of life for symptomatic congenital CMV infection is recommended for improved neurodevelopmental and audiologic outcomes. Birth Defects Research 109:336-346, 2017. © 2017 Wiley Periodicals, Inc.

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HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

Cited by 151 publications

References 45 publications

Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Cytomegalovirus infection in pregnancy

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