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

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.

authors

Murrell I,Bedford C,Ladell K,Miners KL,Price DA,Tomasec P,Wilkinson GWG,Stanton RJ

doi

10.1073/pnas.1704809114

subject

Has Abstract

pub_date

2017-06-06 00:00:00

pages

6104-6109

issue

23

eissn

0027-8424

issn

1091-6490

pii

1704809114

journal_volume

114

pub_type

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