Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 23, Pages 6104-6109Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704809114
Keywords
virology; immune evasion; herpesvirus; HCMV; cell-cell spread
Categories
Funding
- Medical Research Council [MC_UU_12014/3, MR/L018373/1, MR/L008734/1]
- Wellcome Trust [WT090323, WT100326/Z/12/Z]
- NRN Ser Cymru
- Health and Care Research Wales [HS-14-11] Funding Source: researchfish
- Medical Research Council [G1000236, MR/L008734/1, 1427593, G9827961, MC_UU_12014/3, MR/L018373/1, G0700142] Funding Source: researchfish
- Wellcome Trust [090323/Z/09/Z, 100326/Z/12/Z] Funding Source: researchfish
- MRC [G0700142, G1000236, MC_UU_12014/3, G9827961, MR/L008734/1] Funding Source: UKRI
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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.
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