Dynamics of Virus-Receptor Interactions in Virus Binding, Signaling, and Endocytosis

Boulant, Steeve; Stanifer, Megan L.; Lozach, Pierre‐Yves

doi:10.3390/v7062747

Cited by 163 publications

(161 citation statements)

References 113 publications

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“…These findings are consistent with the idea that cell-type-specific differences in virus-induced cellular signaling result in differential infection outcomes that vary according to cell type. Because cellular signaling has been shown to play a role in the entry processes of several viruses (82), it stands to reason that cell-type-specific differences begin during the entry process itself. Although the specific mode of entry has not yet been examined in CD34 ϩ cells, this certainly appears to be the case among other, more commonly studied cell types.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells

Kim

Collins-McMillen

Buehler

et al. 2017

J Virol

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The establishment of human cytomegalovirus (HCMV) latency and persistence relies on the successful infection of hematopoietic cells, which serve as sites of viral persistence and contribute to viral spread. Here, using blocking antibodies and pharmacological inhibitors, we document that HCMV activation of the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol 3-kinase (PI3K) mediates viral entry into CD34 ϩ human progenitor cells (HPCs), resulting in distinct cellular trafficking and nuclear translocation of the virus compared to that in other immune cells, such as we have documented in monocytes. We argue that the EGFR allows HCMV to regulate the cellular functions of these replication-restricted cells via its signaling activity following viral binding. In addition to regulating HCMV entry/ trafficking, EGFR signaling may also shape the early steps required for the successful establishment of viral latency in CD34 ϩ cells, as pharmacological inhibition of EGFR increases the transcription of lytic IE1/IE2 mRNA while curbing the expression of latency-associated UL138 mRNA. EGFR signaling following infection of CD34 ϩ HPCs may also contribute to changes in hematopoietic potential, as treatment with the EGFR kinase (EGFRK) inhibitor AG1478 alters the expression of the cellular hematopoietic cytokine interleukin 12 (IL-12) in HCMV-infected cells but not in mockinfected cells. These findings, along with our previous work with monocytes, suggest that EGFR likely serves as an important determinant of HCMV tropism for select subsets of hematopoietic cells. Moreover, our new data suggest that EGFR is a key receptor for efficient viral entry and that the ensuing signaling regulates important early events required for successful infection of CD34 ϩ HPCs by HCMV.IMPORTANCE HCMV establishes lifelong persistence within the majority of the human population without causing overt pathogenesis in healthy individuals. Despite this, reactivation of HCMV from its latent reservoir in the bone marrow causes significant morbidity and mortality in immunologically compromised individuals, such as bone marrow and solid organ transplant patients. Lifelong persistent infection has also been linked with the development of various cardiovascular diseases in otherwise healthy individuals. Current HCMV therapeutics target lytic replication, but not the latent viral reservoir; thus, an understanding of the molecular basis for viral latency and persistence is paramount to controlling or eliminating HCMV infection. Here, we show that the viral signalosome activated by HCMV binding to its entry re-

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells

Kim

Collins-McMillen

Buehler

et al. 2017

J Virol

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“…Virus entry constitutes a series of interactions between a virion and its host cell occurring early in the viral life cycle (Boulant et al, 2015;Grove and Marsh, 2011;Hofmann and Pöhlmann, 2004;Marsh and Helenius, 2006). For an enveloped virus, these steps allow the virus to (i) bind to a target host cell, typically via interactions with cellular receptors, (ii) fuse its envelope with a cellular membrane, either at the plasma membrane or through the endocytic pathway, and (iii) deliver its genetic material inside the cell.…”

Section: Introductionmentioning

confidence: 99%

Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells

2018

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During viral entry, enveloped viruses require the fusion of their lipid envelope with host cell membranes. For coronaviruses, this critical step is governed by the virally-encoded spike (S) protein, a class I viral fusion protein that has several unique features. Coronavirus entry is unusual in that it is often biphasic in nature, and can occur at or near the cell surface or in late endosomes. Recent advances in structural, biochemical and molecular biology of the coronavirus S protein has shed light on the intricacies of coronavirus entry, in particular the molecular triggers of coronavirus S-mediated membrane fusion. Furthermore, characterization of the coronavirus fusion peptide (FP), the segment of the fusion protein that inserts to a target lipid bilayer during membrane fusion, has revealed its particular attributes which imparts some of the unusual properties of the S protein, such as Ca-dependency. These unusual characteristics can explain at least in part the biphasic nature of coronavirus entry. In this review, using severe acute respiratory syndrome coronavirus (SARS-CoV) as model virus, we give an overview of advances in research on the coronavirus fusion peptide with an emphasis on its role and properties within the biological context of host cell entry.

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“…Similar mechanisms that exploit ECM remodeling have evolved to enable entry of other moieties and signals into cells with high efficiency. Viruses bind to ECM to enhance their cellular availability, preserve their stability, and increase the chance of internalization via interaction with specific cellular receptors [21, 25, 26], and ECM endocytic pathways are also commonly used to facilitate cellular uptake of viruses via integrin-dependent pathways [21, 25, 26], especially via collagen-binding integrins such as α 2 β 1 [26, 27]. ECM components have even been found to act as bridges that directly facilitate binding and initiate viral internalization [21].…”

Section: Introductionmentioning

confidence: 99%

ECM turnover-stimulated gene delivery through collagen-mimetic peptide-plasmid integration in collagen

2017

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Gene therapies have great potential in regenerative medicine; however, clinical translation has been inhibited by low stability and limited transfection efficiencies. Herein, we incorporate collagen-mimetic peptide (CMP)-linked polyplexes in collagen scaffolds to increase DNA stability by up to 400% and enable tailorable in vivo transgene expression at 100-fold higher levels and 10-fold longer time periods. These improvements were directly linked to a sustained interaction between collagen and polyplexes that persisted during cellular remodeling, polyplex uptake, and intracellular trafficking. Specifically, incorporation of CMPs into polyethylenimine (PEI) polyplexes preserved serum-exposed polyplex-collagen activity over a period of 14 days, with 4 orders-of-magnitude more intact DNA present in CMP-modified polyplex-collagen relative to unmodified polyplex-collagen after a 10 day incubation under cell culture conditions. CMP-modification also altered endocytic uptake, as indicated by gene silencing studies showing a nearly 50% decrease in transgene expression in response to caveolin-1 silencing in modified samples versus only 30% in unmodified samples. Furthermore, cellular internalization studies demonstrated that polyplex-collagen association persisted within cells in CMP polyplexes, but not in unmodified polyplexes, suggesting that CMP linkage to collagen regulates intracellular transport. Moreover, experiments in an in vivo repair model showed that CMP modification enabled tailoring of transgene expression from 4 to 25 days over a range of concentrations. Overall, these findings demonstrate that CMP decoration provides substantial improvements in gene retention, altered release kinetics, improved serum-stability, and improved gene activity in vivo. This versatile technique has great potential for multiple applications in regenerative medicine.

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Dynamics of Virus-Receptor Interactions in Virus Binding, Signaling, and Endocytosis

Cited by 163 publications

References 113 publications

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells

Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells

ECM turnover-stimulated gene delivery through collagen-mimetic peptide-plasmid integration in collagen

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Dynamics of Virus-Receptor Interactions in Virus Binding, Signaling, and Endocytosis

Cited by 163 publications

References 113 publications

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 + Human Progenitor Cells

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 + Human Progenitor Cells

Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells

ECM turnover-stimulated gene delivery through collagen-mimetic peptide-plasmid integration in collagen

Contact Info

Product

Resources

About

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells