Biology subjects

Aaskov, J.

Publications and source records attributed to Aaskov, J..

4 recordsLinked to original sources

bioRxiv2020

Minimising severity of dengue serotype 1 infection bytransmissible interfering particles

Transmissible 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.

developmental biology↗

bioRxiv2019

Administration of defective virus via bang-bang optimal control inhibits dengue transmission

The host-vector shuttle and the bottleneck in dengue transmission is a significant aspect with regard to the study of dengue outbreaks. As mosquitoes require 100-1000 times more virus to become infected than human, the transmission of dengue virus from human to mosquito is a vulnerability that can be targeted to improve disease control. In order to capture the heterogeneity in the infectiousness of an infected patient population towards the mosquito pool, we calibrate a population of host-to-vector virus transmission models based on an experimentally quantified infected fraction of a mosquito population. Once the population of models is well-calibrated, we deploy a population of controls that helps to inhibit the human-to-mosquito transmission of the dengue virus indirectly by reducing the viral load in the patient body fluid. We use an optimal bang-bang control on the administration of the defective virus (transmissible interfering particles, known as TIPs) to symptomatic patients in the course of their febrile period and observe the dynamics in successful reduction of dengue spread into mosquitoes.

systems biology↗

bioRxiv2018

A population of bang-bang switches of defective interfering particles makes within-host dynamics of dengue virus controllable

The titre of virus in a dengue patient and the duration of this viraemia has a profound effect on whether or not a mosquito will become infected when it feeds on the patient and this, in turn is a key driver of the magnitude of a dengue outbreak. As mosquitoes require 100-1000 times more virus to become infected than a patient, the transmission of dengue virus from a patient to a mosquito is a vulnerability that may be able to be targeted to improve disease control. The intrinsic variability in the within-host dynamics of viraemias is explored for a population of patients using the method of population of models (POMs). A dataset from 207 patients is used to calibrate 20,000 models for the infection kinetics for each of the four dengue virus serotypes. The effect of adding defective dengue virus interfering particles to patients as a therapeutic is evaluated using the calibrated POMs in a bang-bang optimal control setting.\n\nAuthor summaryDengue virions with deletions or defects in their genomes can be recovered from dengue patients. These defective viruses can only replicate with the assistance of fully functional viruses and they reduce the yield of the fully functional viruses. They are known as defective interfering (DI) particles. By administering additional, defined, DI particles to patients it may be possible to reduce the titre and duration of their viraemia. This, in turn may reduce the severity of the disease and the likelihood that dengue virus will be passed from the patient to a mosquito vector. This study estimates the number of DI particles that would need to be administered, and over what period, to have a significant effect on patient viraemia and subsequent dengue fever severity.

systems biology↗

bioRxiv2018

Using paired serology and surveillance data to quantify dengue transmission and control during a large outbreak in Fiji

Dengue is a major health burden, but it can be challenging to examine transmission dynamics and evaluate control measures because outbreaks depend on multiple factors, including human population structure, prior immunity and climate. We combined population-representative paired sera collected before and after the major 2013/14 dengue-3 outbreak in Fiji with surveillance data to determine how such factors influence dengue virus transmission and control in island settings. Our results suggested the 10-19 year-old age group had the highest risk of acquiring infection, but we did not find strong evidence that other demographic or environmental risk factors were linked to seroconversion. Mathematical modelling showed that temperature-driven variation in transmission and herd immunity could not fully explain observed dynamics. However, there was evidence of an additional reduction in transmission coinciding with a vector clean-up campaign, which may have contributed to the decline in cases and prevented transmission continuing into the following season.

epidemiology↗