Human cytomegalovirus gH/gL/UL128/UL130/UL131A complex elicits potently neutralizing antibodies in mice

Wen, Yingxia; Monroe, James E.; Linton, Christine; Archer, Jacob; Beard, Clayton W.; Barnett, Susan W.; Palladino, Giuseppe; Mason, Peter W.; Carfı́, Andrea; Lilja, Anders

doi:10.1016/j.vaccine.2014.05.004

Cited by 75 publications

(77 citation statements)

References 37 publications

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“…1). Consistent with previous reports (24,32,35,36), this analysis revealed that HCMV gH and gL are covalently linked by disulfide bonds and that additional disulfides form between two gH/gL complexes. For simplicity, these dimers of gH/gL heterodimers will be referred to as gH/gL homodimers (Fig.…”

supporting

confidence: 91%

“…We concluded that the mutations introduced do not affect cellsurface expression and overall Pentamer structure. Consistent with these data, purified Pentamer containing both gL-Cys-144-Ser and UL128-Cys-162-Ser was antigenically equivalent to the WT protein (32). Together, the interference and syncytia data suggest that mutations of both gL-Cys-144 and UL128-Cys-162 affect Pentamer interaction with host factors and its function in cell entry.…”

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

confidence: 67%

“…In addition, several studies have demonstrated that the Pentamer is the main target of the neutralizing humoral response to HCMV infection in epithelial/endothelial cells (27)(28)(29). Consistent with these observations, immunization with the Pentamer has been shown to elicit a strong neutralizing antibody response in mouse, rabbit, and rhesus macaque models (30)(31)(32). Together these data indicate that the Pentamer represents a key antigenic target for vaccine development against HCMV infection.…”

supporting

confidence: 54%

“…We have recently shown that mice immunized with MF59 adjuvanted Pentamer protein raise high neutralizing antibody titers (32). These neutralizing responses were comparable to those observed in seropositive subjects and were 4-, 10-, and 90-fold more potent than those obtained with adjuvanted gH/gL in mice, rabbits, and cotton rats, respectively.…”

Section: Discussionmentioning

confidence: 55%

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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.

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138

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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supporting

confidence: 91%

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

confidence: 67%

supporting

confidence: 54%

Section: Discussionmentioning

confidence: 55%

See 2 more Smart Citations

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.

Self Cite

138

189

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“…When VRPs encoding gH/ gL or PC were compared with the two complexes in the presence or absence of MF59 adjuvant, it was found that VRPs expressing PC produced higher levels of Nt antibodies than those expressing gH/gL, and that MF59 significantly increased the potency of each complex [101,102]. Moreover, non-infectious dense bodies containing both virion tegument and envelope proteins harvested from culture supernatants of AD169 or Towne-infected HELFs, were tested in small animals, showing that both Nt and cellular immune responses are able to prevent infection of both HELFs and epithelial cells [103].…”

Section: Development Of An Hcmv Vaccine: Potential Role Of the Pcmentioning

confidence: 99%

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, L-viremia and L-DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild-type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb¢ region of the HCMV genome. Using bacterial artificial chromosome technology, it was shown by both gain-of-function and loss-of-function experiments that UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. In addition, a number of clinical isolates passaged in human fibroblasts had lost both properties (leuko-tropism and endothelial cell-tropism) when displaying a mutation in the UL131-128 locus

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Current Status of Cytomegalovirus Vaccines: 2016

Schleiss

2016

Encyclopedia of Life Sciences

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A vaccine against the debilitating effects of congenital cytomegalovirus (CMV) infection is a major public health priority. Vaccines against CMV may also improve the outcome of solid organ and haematopoietic stem‐cell transplantation. In spite of the long‐recognised morbidity caused by CMV infection, progress towards a licenced vaccine has been slow, owing to uncertainties about the key immunological correlates of protective immunity and the optimal vaccine expression approaches to employ. Driven by the encouraging (albeit suboptimal) benefit conferred by a recombinant CMV glycoprotein B (gB) vaccine against CMV infection and disease in recent clinical trials, there is currently increased interest in designing and evaluating a number of candidate vaccines in both preclinical models and controlled trials. Several new CMV vaccine candidates are currently undergoing evaluation in clinical trials. Major challenges must be met before a vaccine can be licenced. Chief among these challenges are: (1) the need to define the optimal constituents of CMV vaccines; (2) the need to define the metrics of protection that would be required for licensure of a vaccine for congenital CMV infection and (3) the necessity of solving the challenge of designing successful vaccines against reinfection. Key Concepts Congenital infection with CMV is the most common congenital viral infection and is responsible for a wide range of birth defects, including sensorineural hearing loss, mental retardation and developmental delay. Primary infection with CMV during pregnancy confers the greatest risk of foetal transmission, but recurrent infections are also common, and these infections can also lead to transmission of CMV with attendant disabilities. Immunity to CMV is complex, and involves both cellular and humoral immune responses. CMV encodes immune evasion genes that complicate the development of protective immunity, help promote reinfection and create challenges for vaccine design. A vaccine for congenital CMV is a major public health priority, but no licenced vaccines exist. Key targets of the humoral immune response to CMV and the cellular immune response include envelope glycoproteins, particularly gB and the PC proteins, and the pp65 and IE1 proteins, respectively. Several clinical trials of both live, attenuated CMV vaccines and subunit vaccines based on recombinant and/or vectored expression of specific immunogens have been conducted. Modest protection against CMV infection has been demonstrated by a recombinant, adjuvanted gB protein subunit vaccine, although the magnitude and duration of protection were suboptimal. Greater public awareness of congenital CMV is required to help drive efforts to develop and licence a protective vaccine.

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Human cytomegalovirus gH/gL/UL128/UL130/UL131A complex elicits potently neutralizing antibodies in mice

Cited by 75 publications

References 37 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 pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Current Status of Cytomegalovirus Vaccines: 2016

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