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Virus-Cell Interactions

Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread

Nicholas T. Streck, Yuanjun Zhao, Jeffrey M. Sundstrom, Nicholas J. Buchkovich
Felicia Goodrum, Editor
Nicholas T. Streck
aDepartment of Microbiology & Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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Yuanjun Zhao
bDepartment of Ophthalmology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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Jeffrey M. Sundstrom
bDepartment of Ophthalmology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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Nicholas J. Buchkovich
aDepartment of Microbiology & Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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Felicia Goodrum
University of Arizona
Roles: Editor
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DOI: 10.1128/JVI.00609-20
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ABSTRACT

Human cytomegalovirus (HCMV) manipulates cellular processes associated with secretory pathways within an infected cell to facilitate efficient viral replication. However, little is known about how HCMV infection alters the surrounding cellular environment to promote virus spread to uninfected cells. Extracellular vesicles (EVs) are key signaling molecules that are commonly altered in numerous disease states. Previous reports have shown that viruses commonly alter EVs, which can significantly impact infection. This study finds that HCMV modulates EV biogenesis machinery through upregulation of the endosomal sorting complex required for transport (ESCRT) proteins. This regulation appears to increase the activity of EV biogenesis, since HCMV-infected fibroblasts have increased vesicle release and altered vesicle size compared to EVs from uninfected cells. EVs generated through ESCRT-independent pathways are also beneficial to virus spread in fibroblasts, as treatment with the EV inhibitor GW4869 slowed the efficiency of HCMV spread. Importantly, the transfer of EVs purified from HCMV-infected cells enhanced virus spread. This suggests that HCMV modulates the EV pathway to transfer proviral signals to uninfected cells that prime the cellular environment for incoming infection and enhance the efficiency of virus spread.

IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus that leads to serious health consequences in neonatal or immunocompromised patients. Clinical management of infection in these at-risk groups remains a serious concern even with approved antiviral therapies available. It is necessary to increase our understanding of the cellular changes that occur during infection and their importance to virus spread. This may help to identify new targets during infection that will lead to the development of novel treatment strategies. Extracellular vesicles (EVs) represent an important method of intercellular communication in the human host. This study finds that HCMV manipulates this pathway to increase the efficiency of virus spread to uninfected cells. This finding defines a new layer of host manipulation induced by HCMV infection that leads to enhanced virus spread.

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Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread
Nicholas T. Streck, Yuanjun Zhao, Jeffrey M. Sundstrom, Nicholas J. Buchkovich
Journal of Virology Jul 2020, 94 (16) e00609-20; DOI: 10.1128/JVI.00609-20

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Human Cytomegalovirus Utilizes Extracellular Vesicles To Enhance Virus Spread
Nicholas T. Streck, Yuanjun Zhao, Jeffrey M. Sundstrom, Nicholas J. Buchkovich
Journal of Virology Jul 2020, 94 (16) e00609-20; DOI: 10.1128/JVI.00609-20
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KEYWORDS

CD63
ESCRTs
GW4869
HCMV
extracellular vesicles
spread

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