The pentameric complex drives immunologically covert cell -cell transmission of wild-type human cytomegalovirus

Murrell, Isa, Bedford, Carmen, Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Miners, Kelly L., Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Tomasec, Peter, Wilkinson, Gavin W. G. ORCID: https://orcid.org/0000-0002-5623-0126 and Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182 2017. The pentameric complex drives immunologically covert cell -cell transmission of wild-type human cytomegalovirus. Proceedings of the National Academy of Sciences 114 (23) , pp. 6104-6109. 10.1073/pnas.1704809114

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Abstract

Human cytomegalovirus (HCMV) strains that have been passaged in vitro rapidly acquire mutations that impact viral growth. These laboratory-adapted strains of HCMV generally exhibit restricted tropism, produce high levels of cell-free virus, and develop susceptibility to natural killer cells. To permit experimentation with a virus that retained a clinically relevant phenotype, we reconstructed a wild-type (WT) HCMV genome using bacterial artificial chromosome technology. Like clinical virus, this genome proved to be unstable in cell culture; however, propagation of intact virus was achieved by placing the RL13 and UL128 genes under conditional expression. In this study, we show that WT-HCMV produces extremely low titers of cell-free virus but can efficiently infect fibroblasts, epithelial, monocyte-derived dendritic, and Langerhans cells via direct cell–cell transmission. This process of cell–cell transfer required the UL128 locus, but not the RL13 gene, and was significantly less vulnerable to the disruptive effects of IFN, cellular restriction factors, and neutralizing antibodies compared with cell-free entry. Resistance to neutralizing antibodies was dependent on high-level expression of the pentameric gH/gL/gpUL128–131A complex, a feature of WT but not passaged strains of HCMV.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	virology | immune evasion | herpesvirus | HCMV | cell–cell spread
Additional Information:	PDF uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/1091-6490/(accessed 26.5.17).
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Funders:	MRC, Wellcome
Date of First Compliant Deposit:	24 May 2017
Date of Acceptance:	24 April 2017
Last Modified:	06 Nov 2024 21:30
URI:	https://orca.cardiff.ac.uk/id/eprint/100837

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