Antibody inhibition of human cytomegalovirus spread in epithelial cell cultures

Cui, Xiaohong; Lee, Ronzo; Adler, Stuart P.; McVoy, Michael A.

doi:10.1016/j.jviromet.2013.04.015

Cited by 35 publications

(38 citation statements)

References 46 publications

(97 reference statements)

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“…However, just as viral entry is cell type specific, the mechanisms of cell-to-cell spread may also differ between cell types. Several studies suggest that cell-to-cell spread of CMV in endothelial cell cultures is sensitive to antibody inhibition (34,39,46,47), while we and others have shown that antibodies can limit the spread of CMV in epithelial cell cultures (48)(49)(50).…”

mentioning

confidence: 68%

“…CMV spread in epithelial cells involves gB, gH, and the pentamer, and antibody inhibition of spread closely correlates with neutralizing activity. In a recent study, we showed that HIG or sera from naturally infected subjects can restrict CMV spread in epithelial cell cultures (48). To identify viral factors involved in epithelial cell spread and to determine whether any of our antibodies were discordant with respect to inhibition of epithelial cell entry versus spread, each was assayed for epithelial cell entryneutralizing activity and spread inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Virus HB15-t178b is a nonepithelial cell-tropic pentamer-negative variant of strain AD169 (36). Viruses TS15-rN and TS15-rR are epithelial cell-tropic variants of CMV strain Towne in which a mutation in UL130 has been repaired (48). Virus ABV is an epithelial cell-adapted variant of CMV clinical isolate Uxc (48) (X. Cui and M. A. McVoy, unpublished data).…”

Section: Methodsmentioning

confidence: 99%

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Impact of Antibodies and Strain Polymorphisms on Cytomegalovirus Entry and Spread in Fibroblasts and Epithelial Cells

Cui

Freed

Wang

et al. 2017

J Virol

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Cytomegalovirus (CMV) entry into fibroblasts differs from entry into epithelial cells. CMV also spreads cell to cell and can induce syncytia. To gain insights into these processes, 27 antibodies targeting epitopes in CMV virion glycoprotein complexes, including glycoprotein B (gB), gH/gL, and the pentamer, were evaluated for their effects on viral entry and spread. No antibodies inhibited CMV spread in fibroblasts, including those with potent neutralizing activity against fibroblast entry, while all antibodies that neutralized epithelial cell entry also inhibited spread in epithelial cells and a correlation existed between the potencies of these two activities. This suggests that exposure of virions to the cell culture medium is obligatory during spread in epithelial cells but not in fibroblasts. In fibroblasts, the formation of syncytiumlike structures was impaired not only by antibodies to gB or gH/gL but also by antibodies to the pentamer, suggesting a potential role for the pentamer in promoting fibroblast fusion. Four antibodies reacted with linear epitopes near the N terminus of gH, exhibited strain specificity, and neutralized both epithelial cell and fibroblast entry. Five other antibodies recognized conformational epitopes in gH/gL and neutralized both fibroblast and epithelial cell entry. That these antibodies were strain specific for neutralizing fibroblast but not epithelial cell entry suggests that polymorphisms external to certain gH/gL epitopes may influence antibody neutralization during fibroblast but not epithelial cell entry. These findings may have implications for elucidating the mechanisms of CMV entry, spread, and antibody evasion and may assist in determining which antibodies may be most efficacious following active immunization or passive administration.IMPORTANCE Cytomegalovirus (CMV) is a significant cause of birth defects among newborns infected in utero and morbidity and mortality in transplant and AIDS patients. Monoclonal antibodies and vaccines targeting humoral responses are under development for prophylactic or therapeutic use. The findings reported here (i) confirm that cell-to-cell spread of CMV is sensitive to antibody inhibition in epithelial cells but not fibroblasts, (ii) demonstrate that antibodies can restrict the formation in vitro of syncytiumlike structures that resemble syncytial cytomegalic cells that are associated with CMV disease in vivo, and (iii) reveal that neutralization of CMV by antibodies to certain epitopes in gH or gH/gL is both strain and cell type dependent and can be governed by polymorphisms in sequences external to the epitopes. These findings serve to elucidate the mechanisms of CMV entry, spread, and antibody evasion and may have important implications for the development of CMV vaccines and immunotherapeutics.

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confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Impact of Antibodies and Strain Polymorphisms on Cytomegalovirus Entry and Spread in Fibroblasts and Epithelial Cells

Cui

Freed

Wang

et al. 2017

J Virol

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“…Antibodies directed to CMV limit cell-to-cell spread in endothelial cells (180)(181)(182) and epithelial cells (183), as evidenced by a lack of focal spread in the presence of CMV-neutralizing antibodies, although virus strains may exhibit various degrees of sensitivity. Cell-to-cell spread in fibroblasts, in contrast, may proceed through transient microfusion events (173) and are largely insensitive to antibody-mediated inhibition (138,163,180,(183)(184)(185).…”

Section: Cell-to-cell Spread Avoids Antibody-mediated Inhibitionmentioning

confidence: 99%

“…Cell-to-cell spread in fibroblasts, in contrast, may proceed through transient microfusion events (173) and are largely insensitive to antibody-mediated inhibition (138,163,180,(183)(184)(185). Given the cell-type-specific mechanisms of CMV entry, it is not surprising that the virus exhibits cell-type-dependent mechanisms of cell-to-cell spread.…”

Section: Cell-to-cell Spread Avoids Antibody-mediated Inhibitionmentioning

confidence: 99%

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Gardner

Tortorella

2016

Microbiol Mol Biol Rev

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SUMMARYThe prototypic herpesvirus human cytomegalovirus (CMV) exhibits the extraordinary ability to establish latency and maintain a chronic infection throughout the life of its human host. This is even more remarkable considering the robust adaptive immune response elicited by infection and reactivation from latency. In addition to the ability of CMV to exist in a quiescent latent state, its persistence is enabled by a large repertoire of viral proteins that subvert immune defense mechanisms, such as NK cell activation and major histocompatibility complex antigen presentation, within the cell. However, dissemination outside the cell presents a unique existential challenge to the CMV virion, which is studded with antigenic glycoprotein complexes targeted by a potent neutralizing antibody response. The CMV virion envelope proteins, which are critical mediators of cell attachment and entry, possess various characteristics that can mitigate the humoral immune response and prevent viral clearance. Here we review the CMV glycoprotein complexes crucial for cell attachment and entry and propose inherent properties of these proteins involved in evading the CMV humoral immune response. These include viral glycoprotein polymorphism, epitope competition, Fc receptor-mediated endocytosis, glycan shielding, and cell-to-cell spread. The consequences of CMV virion glycoprotein-mediated immune evasion have a major impact on persistence of the virus in the population, and a comprehensive understanding of these evasion strategies will assist in designing effective CMV biologics and vaccines to limit CMV-associated disease.

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Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo

et al. 2017

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Human cytomegalovirus (HCMV) is an important opportunistic pathogen in immunocompromised patients and a major cause of congenital birth defects when acquired in utero. In the 1990s, four chimeric viruses were constructed by replacing genome segments of the high passage Towne strain with segments of the low passage Toledo strain, with the goal of obtaining live attenuated vaccine candidates that remained safe but were more immunogenic than the overly attenuated Towne vaccine. The chimeras were found to be safe when administered to HCMV-seronegative human volunteers, but to differ significantly in their ability to induce seroconversion. This suggests that chimera-specific genetic differences impacted the ability to replicate or persist in vivo and the consequent ability to induce an antibody response. To identify specific genomic breakpoints between Towne and Toledo sequences and establish whether spontaneous mutations or rearrangements had occurred during construction of the chimeras, complete genome sequences were determined. No major deletions or rearrangements were observed, although a number of unanticipated mutations were identified. However, no clear association emerged between the genetic content of the chimeras and the reported levels of vaccine-induced HCMV-specific humoral or cellular immune responses, suggesting that multiple genetic determinants are likely to impact immunogenicity. In addition to revealing the genome organization of the four vaccine candidates, this study provided an opportunity to probe the genetics of HCMV attenuation in humans. The results may be valuable in the future design of safe live or replication-defective vaccines that optimize immunogenicity and efficacy.

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Antibody inhibition of human cytomegalovirus spread in epithelial cell cultures

Cited by 35 publications

References 46 publications

Impact of Antibodies and Strain Polymorphisms on Cytomegalovirus Entry and Spread in Fibroblasts and Epithelial Cells

Impact of Antibodies and Strain Polymorphisms on Cytomegalovirus Entry and Spread in Fibroblasts and Epithelial Cells

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo

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