Minimising severity of dengue serotype 1 infection by transmissible interfering particles

Abstract

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.