Dengue type 1 viruses circulating in humans are highly infectious and poorly neutralized by human antibodies

Abstract

The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses of humans. The interactions between DENVs and the human host that lead to asymptomatic, mild, or severe disease are poorly understood, in part, because laboratory models are poor surrogates for human DENV disease. Virologists are interested in how the properties of DENVs replicating in people compare with virions propagated on laboratory cell lines, which are widely used for research and vaccine development. Using clinical samples from a DENV type 1 epidemic in Sri Lanka and new ultrasensitive assays, we compared the properties of DENVs in human plasma and after one passage on laboratory cell lines. DENVs in plasma were 50- to 700-fold more infectious than cell culture-grown viruses. DENVs produced by laboratory cell lines were structurally immature and hypersensitive to neutralization by human antibodies compared with DENVs circulating in people. Human plasma and cell culture-derived virions had identical genome sequences, indicating that these phenotypic differences were due to the mature state of plasma virions. Several dengue vaccines are under development. Recent studies indicate that vaccine-induced antibodies that neutralized DENVs in cell culture assays were not sufficient for protecting people from DENV infections. Our results about structural differences between DENVs produced in humans versus cell lines may be key to understanding vaccine failure and developing better models for vaccine evaluation.

Chronic Dengue Virus Panencephalitis in a Patient with Progressive Dementia with Extrapyramidal Features

“…Therefore, the detection of DENV within the biopsy tissue suggests that a persistent infection was established prior to immune suppression and that this infection did not arise from later therapeutic attempts. 29 Together, the observations from our patient and other flaviviruses suggest that virus within the host may be resistant to immune pressures and that the CNS may be an underappreciated anatomical reservoir for flaviviruses. For example, West Nile virus has been detected intermittently in urine up to 6 years postinfection in patients with previous West Nile virus encephalitis.…”

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications

“…However, it is noted that ZIKV RVPs are made in defined cell types (typically BHK cells), and there is evidence suggesting that some flavivirus properties, particularly maturity, can be influenced by the producing cell type (whether live virus or RVP) (47).…”

“…Maturation of flaviviruses occurs by the cleavage of the prM protein to M (9), but this is generally incomplete, with virus maturity (whether live virus or RVP) (Cherrier 2009; ref for ZIKV) being influenced by the producing cell type (Dejninarattisai et al, 2015). In addition, patient-derived DENV showed higher levels of maturity compared with the same virus following passage in cells (47,48). The maturation state of flaviviruses is thought to be important for infectivity and for neutralization by sera in clinical studies.…”

Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

“…However, the suboptimal efficacy and safety profile of a recently licensed DENV vaccine has been partly attributed to its inability to generate a balanced neutralizing antibody response to all four serotypes (Hadinegoro et al, 2015). Additionally, there may be important antigenic differences between circulating and lab-adapted strains (Lim et al, 2019;Raut et al, 2019), as well as among strains even within a given serotype (Bell, Katzelnick, & Bedford, 2019;Katzelnick et al, 2015). Antigenic mismatch between vaccine and circulating strains impacted vaccine efficacy (Juraska et al, 2018), highlighting the importance of rational selection of vaccine components.…”

“…J9 and J8 also potently neutralized contemporary DENV1-4 isolates with IC50 values < 50 ng/ml ( Figure S3). Additionally, in contrast to C4 and the crossreactive DII fusion loop-specific mouse mAb E60 (Goo, VanBlargan, Dowd, Diamond, & Pierson, 2017;Nelson et al, 2008;Oliphant et al, 2006), but similar to EDE bNAbs (Dejnirattisai et al, 2015), J9 and J8 potently neutralized DENV regardless of virion maturation state ( Figure S4), which can indirectly modulate epitope exposure (Cherrier et al, 2009;Goo et al, 2019;Nelson et al, 2008) and has been shown to be distinct among circulating versus labadapted strains (Raut et al, 2019). We also tested the ability of mAbs to mediate neutralization after virus attachment to cells, which is characteristic of many potently neutralizing antibodies against flaviviruses (Goo et al, 2019;Nybakken et al, 2005;Sukupolvi-Petty et al, 2010;Vogt et al, 2009;Xu et al, 2017).…”