Cytomegalovirus Vaccine Strain Towne-Derived Dense Bodies Induce Broad Cellular Immune Responses and Neutralizing Antibodies That Prevent Infection of Fibroblasts and Epithelial Cells

Cayatte, Corinne; Schneider-Ohrum, Kirsten; Wang, Zhaoti; Irrinki, Alivelu; Nguyen, Nga; Lu, Janine; Nelson, Christine L.; Servat, Esteban; Gemmell, Lorraine; Citkowicz, Andrzej; Liu, Yi; Hayes, Gregory M.; Woo, Jennifer; Nest, Gary Van; Jin, Hong; Duke, Gregory; McCormick, A. Louise

doi:10.1128/jvi.01554-13

Cited by 47 publications

(66 citation statements)

References 70 publications

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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]. Further, another innovative approach to vaccine development was the activation of both innate and adaptive immunity by a recombinant HCMV strain expressing an NKG2D ligand [104].…”

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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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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“…We and others have demonstrated that noninfectious dense body (DB) preparations are favorable candidates for vaccination (3)(4)(5)(6)(7). These preparations benefit from an adjuvant effect of the particle and a protein composition similar to that of virions and present a reduced risk because they lack viral DNA (vDNA) (3)(4)(5)(6)(7). The neutralizing antibodies induced by vaccination are important in preventing viral entry into susceptible cell types.…”

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confidence: 99%

Production of Cytomegalovirus Dense Bodies by Scalable Bioprocess Methods Maintains Immunogenicity and Improves Neutralizing Antibody Titers

Schneider-Ohrum

Cayatte

Liu

et al. 2016

J Virol

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With the goal of developing a virus-like particle-based vaccine based on dense bodies (DB) produced by human cytomegalovirus (HCMV) infections, we evaluated scalable culture, isolation, and inactivation methods and applied technically advanced assays to determine the relative purity, composition, and immunogenicity of DB particles. Our results increase our understanding of the benefits and disadvantages of methods to recover immunogenic DB and inactivate contaminating viral particles. IMPORTANCEDevelopment of a vaccine to prevent congenital HCMV infection remains a high priority. Vaccination with human cytomegalovirus-derived noninfectious particles, or dense bodies, may constitute a safe vaccination strategy that mimics natural infection. The standard approach for purification of virus particles has been to use a multiple-step, complex gradient that presents a potential barrier to production scale-up and commercialization. In the study described here, we employed an approach that combines treatment with an antiviral terminase inhibitor and purification by a simplified process to produce a vaccine candidate providing broad antiviral humoral and cellular immunity as a foundation for future development.

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“…As a control, HF were infected with WT-TB40/E and treated with 2-bromo-5,6-dichloro-1-(␤-Dribofuranosyl) benzimidazole (BDCRB; a viral terminase inhibitor in HCMV) (36,37) or mock treated. BDCRB selectively inhibits pUL56 and pUL89, thereby blocking viral genome cleavage without affecting viral gene expression or capsid and dense body formation (24,(38)(39)(40)(41)(42). The presence of the 4.4-and 4.5-kb terminal fragment in WT-TB40/E digested with EcoRI and KpnI, respectively, indicates the occurrence of genome cleavage.…”

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confidence: 99%

Human Cytomegalovirus pUL93 Is Required for Viral Genome Cleavage and Packaging

DeRussy

Tandon

2015

J Virol

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Human cytomegalovirus (HCMV) pUL93 is essential for virus growth, but its precise function in the virus life cycle is unknown. Here, we characterize a UL93 stop mutant virus (UL93st-TB40/E-BAC) to demonstrate that the absence of this protein does not restrict viral gene expression; however, cleavage of viral DNA into unit-length genomes as well as genome packaging is abolished. Thus, pUL93 is required for viral genome cleavage and packaging.H uman cytomegalovirus (HCMV) protein pUL93, a putative tegument protein, is required for the growth of HCMV (1, 2), but the exact function of this protein is unknown. There is no functional study done to date on HCMV pUL93; however, pUL17, the positional homolog of pUL93 in herpes simplex virus 1 (HSV-1), has been shown to be required for the localization of capsids to the DNA replication compartments in the infected cell nucleus, where viral genome cleavage and packaging take place (3, 4). pUL17 has also been found to interact with pUL25, a homolog of HCMV pUL77, to form the capsid vertex-specific component (CVSC), which is found at the 12 vertices of the icosahedral capsid (4-10). The exact function of the CVSC is currently unknown, but it is thought to aid in capsid stability and nuclear egress (10-13). pUL25-null mutants package viral DNA only transiently and produce mostly empty capsids, while pUL17-null mutants completely abolish DNA packaging (3,14). It is important to note that pUL17 and pUL93 are positional homologs that share only 1.5% sequence identity, 1.9% sequence similarity, and no distinct conserved domains (based on amino acid ClustalW alignment). Moreover, several HCMV proteins have been found to have very different functions compared to their homologs in other herpesviruses, highlighting the importance of studying HCMV proteins independently. For example, HCMV pUL50 and pUL53 were presumed to recruit host protein kinase C (PKC) for disruption of the nuclear lamina based on data from other herpesviruses but were instead found to recruit viral protein kinase pUL97 for this purpose (15). Targeting of essential structural viral proteins holds great promise for the development of antivirals that would be highly specific and effective and also less susceptible to the development of resistance be- Citation DeRussy BM, Tandon R. 2015. Human cytomegalovirus pUL93 is required for viral genome cleavage and packaging.

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Cytomegalovirus Vaccine Strain Towne-Derived Dense Bodies Induce Broad Cellular Immune Responses and Neutralizing Antibodies That Prevent Infection of Fibroblasts and Epithelial Cells

Cited by 47 publications

References 70 publications

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

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

Production of Cytomegalovirus Dense Bodies by Scalable Bioprocess Methods Maintains Immunogenicity and Improves Neutralizing Antibody Titers

Human Cytomegalovirus pUL93 Is Required for Viral Genome Cleavage and Packaging

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