7Chikungunya and Zika viruses are arthropod-borne viruses that pose significant threat to public health. 8 Experimental data show that during in vitro infection both viruses exhibit qualitatively distinct repli-9 cation cycle kinetics. Chikungunya viral load rapidly accumulates within the first several hours post 10 infection whereas Zika virus begins to increase at much later times. We sought to characterize these 11 qualitatively distinct in vitro kinetics of chikungunya and Zika viruses by fitting a family of mathe-12 matical models to time course viral load datasets. We demonstrate that the standard viral kinetic 13 model, which considers that new infections result only from free virus penetrating susceptible cells, 14 does not fit experimental data as well as a model in which the number of virus-infected cells is the 15 primary determinant of infection rate. We provide biologically meaningful quantifications of the main 16 viral kinetic parameters and show that our results support cell-to-cell or localized transmission as a 17 significant contributor to viral infection with chikungunya and Zika viruses. 18 19 Importance 20Mathematical modeling has become a useful tool to tease out information about virus-host interactions 21 and thus complements experimental work in characterizing and quantifying processes within viral 22 replication cycle. Importantly, mathematical models can fill in incomplete data sets and identify key 23 parameters of infection, provided the appropriate model is used. The in vitro time course dynamics of 24 mosquito transmitted viruses, such as chikungunya and Zika, have not been studied by mathematical 25 modeling and thus limits our knowledge about quantitative description of the individual determinants 26 of viral replication cycle. This study employs dynamical modeling framework to show that the rate at 27 1 which cells become virus-infected is proportional to the number or virus-infected cells rather than free 28 extracellular virus in the milieu, a widely accepted assumption in models of viral infections. Using 29 the refined mathematical model in combination with viral load data, we provide quantification of 30 the main drivers of chikungunya and Zika in vitro kinetics. Together, our results bring quantitative 31 understanding of the basic components of chikungunya and Zika virus dynamics. 32 Introduction 33 Chikungunya (CHIKV) and Zika (ZIKV) viruses are arthropod-borne viruses (arbovirus) primarily 34 transmitted through a bite of infected Aedes mosquitoes, and their continuous re-emergence pose an 35 important public health threat. CHIKV was originally isolated in 1953 during an epidemic outbreak 36 in Tanzania [1]. Outbreaks of CHIKV occurred in the western Indian Ocean in 2005-6 [2], India 37 and Italy in 2007 along with several Southeast Asian countries, Pacific regions and the Americas 38 [3]. Similarly, ZIKV was first discovered in 1947 in a Ugandan forest [4]. The first sporadic ZIKV 39 outbreaks outside Africa were reported in the Asia-Pacific region in 2007 [5]...
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