The dinucleotide composition of the Zika virus genome is shaped by conflicting evolutionary pressures in mammalian hosts and mosquito vectors

Most vertebrate RNA viruses show pervasive suppression of CpG and UpA dinucleotides, closely resembling the dinucleotide composition of host cell transcriptomes. In contrast, CpG suppression is absent in both invertebrate mRNA and RNA viruses that exclusively infect arthropods. Arthropod-borne (arbo) viruses are transmitted between vertebrate hosts by invertebrate vectors and thus encounter potentially conflicting evolutionary pressures in the different cytoplasmic environments. Using a newly developed Zika virus (ZIKV) model, we have investigated how demands for CpG suppression in vertebrate cells can be reconciled with potentially quite different compositional requirements in invertebrates and how this affects ZIKV replication and transmission. Mutant viruses with synonymously elevated CpG or UpA dinucleotide frequencies showed attenuated replication in vertebrate cell lines, which was rescued by knockout of the zinc-finger antiviral protein (ZAP). Conversely, in mosquito cells, ZIKV mutants with elevated CpG dinucleotide frequencies showed substantially enhanced replication compared to wild type. Host-driven effects on virus replication attenuation and enhancement were even more apparent in mouse and mosquito models. Infections with CpG- or UpA-high ZIKV mutants in mice did not cause typical ZIKV-induced tissue damage and completely protected mice during subsequent challenge with wild-type virus, which demonstrates their potential as live-attenuated vaccines. In contrast, the CpG-high mutants displayed enhanced replication in Aedes aegypti mosquitoes and a larger proportion of mosquitoes carried infectious virus in their saliva. These findings show that mosquito cells are also capable of discriminating RNA based on dinucleotide composition. However, the evolutionary pressure on the CpG dinucleotides of viral genomes in arthropod vectors directly opposes the pressure present in vertebrate host cells, which provides evidence that an adaptive compromise is required for arbovirus transmission. This suggests that the genome composition of arbo flaviviruses is crucial to maintain the balance between high-level replication in the vertebrate host and persistent replication in the mosquito vector.

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An adaptive compromise - Conflicting evolutionary pressures on arthropod-borne Zika virus dinucleotide composition in mammalian hosts and mosquito vectors

10.1101/2021.02.09.430415 ◽

2021 ◽

Author(s):

Jelke J. Fros ◽

Imke Visser ◽

Bing Tang ◽

Kexin Yan ◽

Eri Nakayama ◽

...

Keyword(s):

Zika Virus ◽

Rna Viruses ◽

Host Cells ◽

Vertebrate Host ◽

Mosquito Vector ◽

Antiviral Protein ◽

Cpg Dinucleotides ◽

Mosquito Cells ◽

Dinucleotide Composition ◽

Cpg Suppression

AbstractMost vertebrate RNA viruses show pervasive suppression of CpG and UpA dinucleotides, closely resembling the dinucleotide composition of host cell transcriptomes. In contrast, CpG suppression is absent in both invertebrate mRNA and RNA viruses that exclusively infect arthropods. Arthropod-borne (arbo) viruses are transmitted between vertebrate hosts by invertebrate vectors and thus encounter potentially conflicting evolutionary pressures in the different cytoplasmic environments. Using a newly developed Zika virus (ZIKV) model, we have investigated how demands for CpG suppression in vertebrate cells can be reconciled with potentially quite different compositional requirements in invertebrates, and how this affects ZIKV replication and transmission.Mutant viruses with synonymously elevated CpG or UpA dinucleotide frequencies showed attenuated replication in vertebrate cell lines, which was rescued by knockout of the zinc-finger antiviral protein (ZAP). Conversely, in mosquito cells, ZIKV mutants with elevated CpG dinucleotide frequencies showed substantially enhanced replication compared to wildtype. Host-driven effects on virus replication attenuation and enhancement were even more apparent in mouse and mosquito models. Infections with CpG-or UpA-high ZIKV mutants in mice did not cause typical ZIKV-induced tissue damage and completely protected mice during subsequent challenge with wildtype virus, which demonstrates their potential as live-attenuated vaccines. In contrast, the CpG-high mutants displayed enhanced replication in Aedes aegypti mosquitoes and a larger proportion of mosquitoes carried infectious virus in their saliva.These findings show that mosquito cells are also capable of discriminating RNA based on dinucleotide composition. However, the evolutionary pressure on the CpG dinucleotides of viral genomes in arthropod vectors directly opposes the pressure present in vertebrate host cells, which provides evidence that an adaptive compromise is required for arbovirus transmission. This suggests that the genome composition of arthropod-borne flaviviruses is crucial to maintain the balance between high-level replication in the vertebrate host and persistent replication in the mosquito vector.

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Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Journal of Virology ◽

10.1128/jvi.00339-17 ◽

2017 ◽

Vol 91 (14) ◽

Cited By ~ 24

Author(s):

Michaela J. Schultz ◽

Sharon Isern ◽

Scott F. Michael ◽

Ronald B. Corley ◽

John H. Connor ◽

...

Keyword(s):

Virus Replication ◽

Zika Virus ◽

Western Hemisphere ◽

Mosquito Cell ◽

Mosquito Vector ◽

Viral Inhibition ◽

Virus Growth ◽

Content Type ◽

Bacterial Endosymbiont ◽

Mosquito Cells

ABSTRACT Mosquito-borne arboviruses are a major source of human disease. One strategy to reduce arbovirus disease is to reduce the mosquito's ability to transmit virus. Mosquito infection with the bacterial endosymbiont Wolbachia pipientis wMel is a novel strategy to reduce Aedes mosquito competency for flavivirus infection. However, experiments investigating cyclic environmental temperatures have shown a reduction in maternal transmission of wMel, potentially weakening the integration of this strain into a mosquito population relative to that of other Wolbachia strains. Consequently, it is important to investigate additional Wolbachia strains. All Zika virus (ZIKV) suppression studies are limited to the wMel Wolbachia strain. Here we show ZIKV inhibition by two different Wolbachia strains: wAlbB (isolated from Aedes albopictus mosquitoes) and wStri (isolated from the planthopper Laodelphax striatellus) in mosquito cells. Wolbachia strain wStri inhibited ZIKV most effectively. Single-cycle infection experiments showed that ZIKV RNA replication and nonstructural protein 5 translation were reduced below the limits of detection in wStri-containing cells, demonstrating early inhibition of virus replication. ZIKV replication was rescued when Wolbachia was inhibited with a bacteriostatic antibiotic. We observed a partial rescue of ZIKV growth when Wolbachia-infected cells were supplemented with cholesterol-lipid concentrate, suggesting competition for nutrients as one of the possible mechanisms of Wolbachia inhibition of ZIKV. Our data show that wAlbB and wStri infection causes inhibition of ZIKV, making them attractive candidates for further in vitro mechanistic and in vivo studies and future vector-centered approaches to limit ZIKV infection and spread. IMPORTANCE Zika virus (ZIKV) has swiftly spread throughout most of the Western Hemisphere. This is due in large part to its replication in and spread by a mosquito vector host. There is an urgent need for approaches that limit ZIKV replication in mosquitoes. One exciting approach for this is to use a bacterial endosymbiont called Wolbachia that can populate mosquito cells and inhibit ZIKV replication. Here we show that two different strains of Wolbachia, wAlbB and wStri, are effective at repressing ZIKV in mosquito cell lines. Repression of virus growth is through the inhibition of an early stage of infection and requires actively replicating Wolbachia. Our findings further the understanding of Wolbachia viral inhibition and provide novel tools that can be used in an effort to limit ZIKV replication in the mosquito vector, thereby interrupting the transmission and spread of the virus.

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Zika Virus Trafficking and Interactions in the Human Male Reproductive Tract

Pathogens ◽

10.3390/pathogens7020051 ◽

2018 ◽

Vol 7 (2) ◽

pp. 51 ◽

Cited By ~ 6

Author(s):

Lucia Da Silva

Keyword(s):

Zika Virus ◽

Reproductive Tract ◽

Sexual Transmission ◽

Host Cells ◽

Future Research ◽

Mosquito Vector ◽

Male Reproductive Tract ◽

Unprotected Sexual Intercourse ◽

Human Male ◽

Viral Interactions

Sexual transmission of Zika virus (ZIKV) is a matter of great concern. Infectious viral particles can be shed in semen for as long as six months after infection and can be transferred to male and female sexual partners during unprotected sexual intercourse. The virus can be found inside spermatozoa and could be directly transferred to the oocyte during fertilization. Sexual transmission of ZIKV can contribute to the rise in number of infected individuals in endemic areas as well as in countries where the mosquito vector does not thrive. There is also the possibility, as has been demonstrated in mouse models, that the vaginal deposition of ZIKV particles present in semen could lead to congenital syndrome. In this paper, we review the current literature to understand ZIKV trafficking from the bloodstream to the human male reproductive tract and viral interactions with host cells in interstitial spaces, tubule walls, annexed glands and semen. We hope to highlight gaps to be filled by future research and potential routes for vaccine and antiviral development.

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The Influenza A Virus M2 Cytoplasmic Tail Is Required for Infectious Virus Production and Efficient Genome Packaging

Journal of Virology ◽

10.1128/jvi.79.6.3595-3605.2005 ◽

2005 ◽

Vol 79 (6) ◽

pp. 3595-3605 ◽

Cited By ~ 127

Author(s):

Matthew F. McCown ◽

Andrew Pekosz

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Infectious Virus ◽

Virus Production ◽

Cytoplasmic Tail ◽

Host Cells ◽

Wild Type Virus ◽

Type Virus ◽

Wild Type ◽

Virus Particles

ABSTRACT The M2 integral membrane protein encoded by influenza A virus possesses an ion channel activity that is required for efficient virus entry into host cells. The role of the M2 protein cytoplasmic tail in virus replication was examined by generating influenza A viruses encoding M2 proteins with truncated C termini. Deletion of 28 amino acids (M2Stop70) resulted in a virus that produced fourfold-fewer particles but >1,000-fold-fewer infectious particles than wild-type virus. Expression of the full-length M2 protein in trans restored the replication of the M2 truncated virus. Although the M2Stop70 virus particles were similar to wild-type virus in morphology, the M2Stop70 virions contained reduced amounts of viral nucleoprotein and genomic RNA, indicating a defect in vRNP packaging. The data presented indicate the M2 cytoplasmic tail plays a role in infectious virus production by coordinating the efficient packaging of genome segments into influenza virus particles.

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Reverse Genetic System for the Analysis of Parvovirus Telomeres Reveals Interactions between Transcription Factor Binding Sites in the Hairpin Stem

Journal of Virology ◽

10.1128/jvi.77.16.8650-8660.2003 ◽

2003 ◽

Vol 77 (16) ◽

pp. 8650-8660 ◽

Cited By ~ 9

Author(s):

Erik Burnett ◽

Peter Tattersall

Keyword(s):

Binding Site ◽

Simian Virus 40 ◽

Viral Fitness ◽

Host Cells ◽

Initiation Factor ◽

Wild Type Virus ◽

Reverse Genetic System ◽

Wild Type ◽

Left Hand ◽

Factor Binding

ABSTRACT The left-hand or 3′-terminal hairpin of minute virus of mice (MVM) contains sequence elements essential for both viral DNA replication at the left-hand origin (oriL) and for the modulation of the P4 promoter, from which the viral nonstructural gene cassette is transcribed. This hairpin sequence has proven difficult to manipulate in the context of the viral genome. Here we describe a system for generating mutant viruses using synthetic hairpin oligonucleotides and a truncated form of the infectious clone. This allows manipulation of the sequence of the left-hand hairpin and examination of the effects in the context of the viral life cycle. We have confirmed the requirement for a functional parvovirus initiation factor (PIF) binding site and determined that an optimized PIF binding site, with 6 bases between the half-sites, was actually detrimental to viral growth. The distal PIF half-site overlaps a cyclic AMP-responsive element (CRE), which was shown to play an important role in initiating infection, particularly in 324K simian virus 40-transformed human fibroblasts. Interestingly, reducing the spacing of the PIF half-sites, and thus the affinity of the binding site for PIF, increased viral fitness relative to wild type in 324K cells, but not in murine A9 cells. These results indicate that the relative importance of factor binding to the CRE and PIF sites during the establishment of an infection differs markedly between these two host cells and suggest that the suboptimal spacing of PIF half-sites found in wild-type virus represents a necessary reduction in the affinity of the PIF interaction in favor of CRE function.

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Identification of Amino Acid Residues in BK Virus VP1 That Are Critical for Viability and Growth

Journal of Virology ◽

10.1128/jvi.01316-07 ◽

2007 ◽

Vol 81 (21) ◽

pp. 11798-11808 ◽

Cited By ~ 39

Author(s):

Aisling S. Dugan ◽

Megan L. Gasparovic ◽

Natia Tsomaia ◽

Dale F. Mierke ◽

Bethany A. O'Hara ◽

...

Keyword(s):

Amino Acids ◽

Sialic Acid ◽

Burst Size ◽

Point Mutations ◽

Bk Virus ◽

Host Cells ◽

Wild Type Virus ◽

Wild Type ◽

Virion Protein ◽

Virus Propagation

ABSTRACT BK virus (BKV) is a ubiquitous pathogen that establishes a persistent infection in the urinary tract of 80% of the human population. Like other polyomaviruses, the major capsid protein of BKV, virion protein 1 (VP1), is critical for host cell receptor recognition and for proper virion assembly. BKV uses a carbohydrate complex containing α(2,3)-linked sialic acid attached to glycoprotein and glycolipid motifs as a cellular receptor. To determine the amino acids important for BKV binding to the sialic acid portion of the complex, we generated a series of 17 point mutations in VP1 and scored them for viral growth. The first set of mutants behaved identically to wild-type virus, suggesting that these amino acids were not critical for virus propagation. Another group of VP1 mutants rendered the virus nonviable. These mutations failed to protect viral DNA from DNase I digestion, indicating a role for these domains in capsid assembly and/or packaging of DNA. A third group of VP1 mutations packaged DNA similarly to the wild type but failed to propagate. The initial burst size of these mutations was similar to that of the wild type, indicating that there is no defect in the lytic release of the mutated virions. Binding experiments revealed that a subset of the BKV mutants were unable to attach to their host cells. These motifs are likely important for sialic acid recognition. We next mapped these mutations onto a model of BKV VP1 to provide atomic insight into the role of these sites in the binding of sialic acid to VP1.

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The Dengue Virus Nonstructural Protein 1 (NS1) Is Secreted from Mosquito Cells in Association with the Intracellular Cholesterol Transporter Chaperone Caveolin Complex

Journal of Virology ◽

10.1128/jvi.01985-18 ◽

2018 ◽

Vol 93 (4) ◽

Cited By ~ 5

Author(s):

Romel Rosales Ramirez ◽

Juan E. Ludert

Keyword(s):

Dengue Virus ◽

Nonstructural Protein ◽

Cell Interactions ◽

Vertebrate Host ◽

Mosquito Vector ◽

Caveolin 1 ◽

Nonstructural Protein 1 ◽

Virion Release ◽

Mosquito Cells ◽

Infected Cells

ABSTRACTDengue virus (DENV) is a mosquito-borne virus of the familyFlaviviridae. The RNA viral genome encodes three structural and seven nonstructural proteins. Nonstructural protein 1 (NS1) is a multifunctional protein actively secreted in vertebrate and mosquito cells during infection. In mosquito cells, NS1 is secreted in a caveolin-1-dependent manner by an unconventional route. The caveolin chaperone complex (CCC) is a cytoplasmic complex formed by caveolin-1 and the chaperones FKBP52, Cy40, and CyA and is responsible for the cholesterol traffic inside the cell. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 associates with and relies on the CCC for secretion. Treatment of mosquito cells with classic secretion inhibitors, such as brefeldin A, Golgicide A, and Fli-06, showed no effect on NS1 secretion but significant reductions in recombinant luciferase secretion and virion release. Silencing the expression of CAV-1 or FKBP52 with short interfering RNAs or the inhibition of CyA by cyclosporine resulted in significant decrease in NS1 secretion, again without affecting virion release. Colocalization, coimmunoprecipitation, and proximity ligation assays indicated that NS1 colocalizes and interacts with all proteins of the CCC. In addition, CAV-1 and FKBP52 expression was found augmented in DENV-infected cells. Results obtained with Zika virus-infected cells suggest that in mosquito cells, ZIKV NS1 follows the same secretory pathway as that observed for DENV NS1. These results uncover important differences in the dengue virus-cell interactions between the vertebrate host and the mosquito vector as well as novel functions for the chaperone caveolin complex.IMPORTANCEThe dengue virus protein NS1 is secreted efficiently from both infected vertebrate and mosquito cells. Previously, our group reported that NS1 secretion in mosquito cells follows an unconventional secretion pathway dependent on caveolin-1. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 secretion takes place in association with the chaperone caveolin complex, a complex formed by caveolin-1 and the chaperones FKBP52, CyA, and Cy40, which are in charge of cholesterol transport inside the cell. Results obtained with ZIKV-infected mosquito cells suggest that ZIKV NS1 is released following an unconventional secretory route in association with the chaperone caveolin complex. These results uncover important differences in the virus-cell interactions between the vertebrate host and the mosquito vector, as well as novel functions for the chaperone caveolin complex. Moreover, manipulation of the NS1 secretory route may prove a valuable strategy to combat these two mosquito-borne diseases.

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The secretory fate of flavivirus NS1 in mosquito cells is influenced by the caveolin binding domain

10.1101/2019.12.16.879031 ◽

2019 ◽

Author(s):

Romel Rosales Ramirez ◽

Juan E. Ludert

Keyword(s):

Yellow Fever ◽

Zika Virus ◽

Yellow Fever Virus ◽

Binding Domain ◽

Expression Vectors ◽

Mosquito Vector ◽

Structural Protein ◽

Aromatic Residues ◽

Secretion Pathway ◽

Mosquito Cells

ABSTRACTFlaviviruses of major medical importance worldwide such as dengue (DENV), Zika (ZIKV), and yellow fever (YFV) viruses are transmitted by mosquitoes Aedes sp. The non-structural protein 1 (NS1) of these flaviviruses is secreted from the infected cells using different secretion routes depending on the cell and virus nature. The NS1 of DENV and ZIKV contain in the hydrophobic region a conserved caveolin binding domain (CBD) (ΦXXΦXXXXΦ), which is not conserved in YFV NS1. To ascertain the role of the CBD in the secretory route followed by flavivirus NS1, expression vectors for the NS1 of DENV2, ZIKV and YFV were constructed. Using site-directed mutagenesis, substitutions were made in the aromatic residues within CBD; in addition, the full domain was replaced by those of other flaviviruses, creating chimeras in the CBD of NS1. Substitutions of the aromatic residues to Ala or Thr, or CBD chimeras, results in increased sensitivity of NS1 secretion to brefeldin A treatment, indicating a change to a classical secretion pathway. Likewise, the insertion of the DENV/ZIKV CBD into the recombinant Gaussia-Luciferase results in a loss of sensitivity to BFA treatment, in luciferase secretion. These results suggest that the CBD sequence is a molecular determinant for the unconventional secretory route followed by DENV and ZIKV NS1 in mosquito cells. However, the cellular components that recognize the CBD in the NS1 of DENV and ZIKV and redirect them to an unconventional route and if this secretion route confers unique functions to NS1 within the vector mosquito are aspects currently unknown.ImportanceFlaviviruses are an important cause of mosquito borne diseases to humans. We have previously demonstrated that the non-structural protein 1 from dengue and zika virus are secreted efficiently from mosquito cells using an unconventional route, that depends on caveolin and molecular chaperones. In this work, we show evidence indicating that a caveolin binding domain, well conserved and exposed in dengue and Zika virus NS1, but absent in other flaviviruses such as yellow fever virus or West Nile virus, is important in determining the unconventional secretion pathway followed by dengue and zika virus NS1 in mosquito cells. The unique secretory pathway followed by NS1 in mosquito cells may result in distinctive viral-cellular protein associations required to facilitate viral infection in the mosquito vector. To identify viral and cellular elements that could disturb the traffic of dengue and Zika virus NS1 may be important to design of strategies for vector control.

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Glycosylation and disulfide bonding of wild-type SARS-CoV-2 spike glycoprotein

Journal of Virology ◽

10.1128/jvi.01626-21 ◽

2021 ◽

Author(s):

Shijian Zhang ◽

Eden P. Go ◽

Haitao Ding ◽

Saumya Anang ◽

John C. Kappes ◽

...

Keyword(s):

Disulfide Bond ◽

Neutralizing Antibodies ◽

Natural Infection ◽

Etiologic Agent ◽

Host Cells ◽

Wild Type Virus ◽

Virus Infectivity ◽

Wild Type ◽

Spike Glycoprotein ◽

Sugar Addition

The SARS-CoV-2 coronavirus, the etiologic agent of COVID-19, uses its spike (S) glycoprotein anchored in the viral membrane to enter host cells. The S glycoprotein is the major target for neutralizing antibodies elicited by natural infection and by vaccines. Approximately 35% of the SARS-CoV-2 S glycoprotein consists of carbohydrate, which can influence virus infectivity and susceptibility to antibody inhibition. We found that virus-like particles produced by co-expression of SARS-CoV-2 S, M, E and N proteins contained spike glycoproteins that were extensively modified by complex carbohydrates. We used a fucose-selective lectin to purify the Golgi-modified fraction of a wild-type SARS-CoV-2 S glycoprotein trimer, and determined its glycosylation and disulfide bond profile. Compared with soluble or solubilized S glycoproteins modified to prevent proteolytic cleavage and to retain a prefusion conformation, more of the wild-type S glycoprotein N-linked glycans are processed to complex forms. Even Asn 234, a significant percentage of which is decorated by high-mannose glycans on other characterized S trimer preparations, is predominantly modified in the Golgi compartment by processed glycans. Three incompletely occupied sites of O-linked glycosylation were detected. Viruses pseudotyped with natural variants of the serine/threonine residues implicated in O-linked glycosylation were generally infectious and exhibited sensitivity to neutralization by soluble ACE2 and convalescent antisera comparable to that of the wild-type virus. Unlike other natural cysteine variants, a Cys15Phe (C15F) mutant retained partial, but unstable, infectivity. These findings enhance our understanding of the Golgi processing of the native SARS-CoV-2 S glycoprotein carbohydrates and could assist the design of interventions. IMPORTANCE The SARS-CoV-2 coronavirus, which causes COVID-19, uses its spike glycoprotein to enter host cells. The viral spike glycoprotein is the main target of host neutralizing antibodies that help to control SARS-CoV-2 infection and are important for the protection provided by vaccines. The SARS-CoV-2 spike glycoprotein consists of a trimer of two subunits covered with a coat of carbohydrates (sugars). Here, we describe the disulfide bonds that assist the SARS-CoV-2 spike glycoprotein to assume the correct shape, and the composition of the sugar moieties on the glycoprotein surface. We also evaluate the consequences of natural virus variation in O-linked sugar addition and in the cysteine residues involved in disulfide bond formation. This information can expedite the improvement of vaccines and therapies for COVID-19.

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Minimising severity of dengue serotype 1 infection by transmissible interfering particles

10.1101/2020.04.21.052936 ◽

2020 ◽

Author(s):

A. Shausan ◽

J. Aaskov ◽

C. Drovandi ◽

K. Mengersen

Keyword(s):

Therapeutic Agent ◽

Antiviral Agent ◽

Host Cells ◽

Wild Type Virus ◽

Parameter Estimates ◽

Type Virus ◽

Wild Type ◽

Significant Difference ◽

Serotype 1

AbstractTransmissible interfering dengue particles (DENV–TIPs) are engineered dengue virus mutants which are defective and can replicate only with the help of dengue wild–type virus (DENV). In vitro studies have found that when DENV–TIPs and DENV coinfect a cell, they compete for viral genomes and cell proteins for replication and packaging, and DENV–TIPs outperform DENV in this process. Thus, it is hypothesised that DENV–TIPs may be used as a novel therapeutic agent. However, the effectiveness of DENV–TIPs as an antiviral agent is yet to be explored at an epidemiological scale. We present a mathematical model for the replication of DENV and DENV–TIPs as they interact with human host cells, accounting for the effectiveness of DENV–TIPs in blocking DENV from coinfected cells. We fit the model to sequentially measured plasma viral titre data from primary and secondary dengue serotype 1 infected patients in Vietnam. We show that variation in initial DENV load is sufficient to recreate the observed variation between patients. Parameter estimates, differing in primary and secondary infections, do not confirm a significant difference between these two types of infection. We use our model to investigate the potential impact of DENV–TIPs as an antiviral agent. We conclude that, when the effectiveness of DENV–TIPs in inhibiting DENV from coinfected cells is at least 80%, a dose as high as 1012 copies per millilitre of blood is required to reduce duration of infection and peak DENV serotype 1 infection level at any time point of infection. This work provides a quantitative understanding of the relationship between DENV–TIPs levels and their efficiency in clearing dengue viral infection. It will guide future development of mechanistic models of how DENV–TIPs might contribute as an antiviral agent in limiting natural dengue infection.Author summaryInhibition of dengue wild–type virus (DENV) by transmissible interfering dengue particles (DENV–TIPs) is seen in some in vitro studies, and it is hypothesised that DENV–TIPs may be used as a therapeutic agent. However, the efficiency of DENV–TIPs in limiting DENV infection in patients is yet to be explored at an epidemiological scale. Using data collected from dengue serotype 1 infected patients, we model how DENV replicates in an infected patient and how effective DENV–TIPs are in controlling that replication. Our results are of use in the evaluation of DENV–TIPs as a potential antiviral agent.

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