Human Cytomegalovirus Glycoprotein gO Complexes with gH/gL, Promoting Interference with Viral Entry into Human Fibroblasts but Not Entry into Epithelial Cells

Vanarsdall, Adam L.; Chase, Marie C.; Johnson, David C.

doi:10.1128/jvi.05659-11

Cited by 77 publications

(88 citation statements)

References 40 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: 55%

“…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%

“…gO is a highly glycosylated protein and has been shown to covalently interact with gH/gL (22,23). It has been proposed that gO might function as a molecular chaperone to promote gH/gL incorporation, but not gH/gL/gO, into the virion (21). However, it has been recently Significance Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and in fetuses after congenital infection.…”

mentioning

confidence: 99%

“…HCMV entry into fibroblasts is mediated by the gH/gL/gO complex at the cell surface at neutral pH (18)(19)(20)(21). gO is a highly glycosylated protein and has been shown to covalently interact with gH/gL (22,23).…”

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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.

142

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: 55%

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

confidence: 99%

mentioning

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.

142

189

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“…Although it was reported to be sufficient (with gB) for entry into fibroblasts (75), a more recent analysis has shown that on the surface of different HCMV strains there are two distinct complexes assembling on the gH/gL scaffold: the trimeric gH/gL/gO and the pentameric gH/gL/UL128/UL130/UL131A complex (76). The efficiency of infection of specific cell types, perhaps by distinct entry pathways, could depend on relative ratios between these complexes on the envelope (76).…”

Section: Discussionmentioning

confidence: 99%

The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

Caló

Cortese

Ciferri³

et al. 2016

J Virol

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Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and is the leading viral cause of birth defects after congenital infection. HCMV infection relies on the recognition of cell-specific receptors by one of the viral envelope glycoprotein complexes. Either the gH/gL/gO or the gH/gL/UL128/UL130/UL131A (Pentamer) complex has been found to fulfill this role, accounting for HCMV entry into almost all cell types. We have studied the UL116 gene product, a putative open reading frame identified by in silico analysis and predicted to code for a secreted protein. Virus infection experiments in mammalian cells demonstrated that UL116 is expressed late in the HCMV replication cycle and is a heavily glycosylated protein that first localizes to the cellular site of virus assembly and then inserts into the virion envelope. Transient-transfection studies revealed that UL116 is efficiently transported to the plasma membrane when coexpressed with gH and that gL competes with UL116 for gH binding. Further evidence for gH/UL116 complex formation was obtained by coimmunoprecipitation experiments on both transfected and infected cells and biochemical characterization of the purified complex. In summary, our results show that the product of the UL116 gene is an HCMV envelope glycoprotein that forms a novel gH-based complex alternative to gH/gL. Remarkably, the gH/UL116 complex is the first herpesvirus gH-based gL-less complex. IMPORTANCE HCMV infection can cause severe disease in immunocompromised adults and infants infected in utero.The dissection of the HCMV entry machinery is important to understand the mechanism of viral infection and to identify new vaccine antigens. The gH/gL/gO and gH/gL/UL128/UL130/UL131 (Pentamer) complexes play a key role in HCMV cell entry and tropism. Both complexes are formed by an invariant gH/gL scaffold on which the other subunits assemble. Here, we show that the UL116 gene product is expressed in infected cells and forms a heterodimer with gH. The gH/UL116 complex is carried on the infectious virions, although in smaller amounts than gH/gL complexes. No gH/UL116/gL ternary complex formed in transfected cells, suggesting that the gH/UL116 complex is independent from gL. This new gH-based gL-free complex represents a potential target for a protective HCMV vaccine and opens new perspectives on the comprehension of the HCMV cell entry mechanism and tropism. H uman cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus infecting 40 to 60% of the human population (1).HCMV infection usually is mild or asymptomatic in immunocompetent individuals, while it can cause severe disease in immunocompromised adults. Infants infected in utero can suffer from disseminated HCMV disease and impaired neurological development (2). Transplant patients do not adequately control HCMV infection or reactivation, often resulting in graft rejection and death (3). Preventing primary HCMV infection could significantly decrease the frequency of organ rejection in seronegative recip...

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Human cytomegalovirus tropism for mucosal myeloid dendritic cells

Hertel¹

2014

Rev. Med. Virol.

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SUMMARY Human CMV infections are a serious source of morbidity and mortality for immunocompromised patients and for the developing fetus. Because of this, the development of new strategies to prevent CMV acquisition and transmission is a top priority. Myeloid dendritic cells (DC) residing in the oral and nasal mucosae are among the first immune cells to encounter CMV during entry, and greatly contribute to virus dissemination, reactivation from latency, and horizontal spread. Albeit affected by the immunoevasive tactics of CMV, mucosal DC remain potent inducers of cellular and humoral immune responses against this virus. Their natural functions could thus be exploited to generate long-lasting protective immunity against CMV by vaccination via the oro-nasal mucosae. Although related, epithelial Langerhans-type DC (LC) and dermal monocyte-derived DC (MDDC) interact with CMV in dramatically different ways. While immature MDDC are fully permissive to infection, for instance, immature LC are completely resistant. Understanding these differences is essential to design innovative vaccines and new antiviral compounds to protect these cells from CMV infection in vivo.

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Human Cytomegalovirus Glycoprotein gO Complexes with gH/gL, Promoting Interference with Viral Entry into Human Fibroblasts but Not Entry into Epithelial Cells

Cited by 77 publications

References 40 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 Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

Human cytomegalovirus tropism for mucosal myeloid dendritic cells

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