1.) Viral spread in complex environments

Several pathogenic viruses are capable of spreading within a host by two different modes of transmission, i.e., cell-free and cell-to-cell spread. To which extent these viruses, such as hepatitis C virus (HCV) or human immunodeficiency virus (HIV), spread by each of the transmission modes, and how target cell tropism and tissue structure affect the transmission dynamics, still remain open questions.

In a series of different projects, we are using mathematical models and computational tools to reveal the processes that determine the spread of infection given different environmental conditions. Thereby, we are using experimental information from different scales to obtain a systematic and quantitative understanding of the individual processes involved.

(a) Quantifying cell-to-cell transmission dynamics HCV spread

To determine the contribution of cell-to-cell transmission for the spread of HCV, we develop mathematical models to analyze in vitro HCV foci spread assays. Using image analysis tools and an individual cell-based model combining intracellular viral replication and intercellular viral spread, we can disentangle the contribution of cell-free and cell-to-cell transmission to viral spread. These analyses might help us to get a better understanding on how individual processes shape infection patterns and, thus, to which extent HCV might spread in vivo. Our analysis also leads to the development of improved methods for quantifying viral spread in the light of cell-to-cell transmission given static cellular conditions. The project is done in close collaboration with Susan L. Uprichard (Loyola University, Chicago) and Karl Rohr (BioQuant-Center) and funded by BIOMS.

  • Kumberger P, Durso-Cain K, Uprichard SL, Dahari H, Graw F: Accounting for space - Quantification of cell-to-cell transmission kinetics using virus dynamics models. Viruses 2018, 10(4). pii E200. doi:10.3390/v10040200
  • Graw F, Martin DN, Perelson AS, Uprichard SL, Dahari H: Quantification of Hepatitis C virus cell-to-cell spread by using a stochastic modeling approach. J Virol 2015, 89:6551-6561
  • Graw F, Balagopal A, Kandathil AJ, Ray SC, Thomas DL, Ribeiro RM, Perelson AS Inferring viral dynamics in chronically HCV infected patients from the spatial distribution of infected hepatocytes. PLoS Comp Biol 2014, 10(11):e1003934

(b) Influence of tissue-structures on the spread of HIV-1

In a project together with Oliver Fackler (University Hospital Heidelberg) and Ulrich Schwarz (BioQuant-Center), we are analyzing the kinetics and contribution of cell-to-cell transmission to HIV-1 infection. In particular, we are interested how different environmental conditions affect these dynamics. By combining time-lapse microscopy data and time-course infection data for the spread of HIV-1 within 3D in vitro cultures, we developed a spatially explicit individual cell-based mathematical model that is able to recapitulate the observed infection dynamics. Based on this model, we are able to link single-cell characteristics to cell population dynamics, and to determine and quantify aspects of the viral transmission process that cannot be obtained experimentally so far. Hereby, we observe that environmental conditions play an important role for the infection dynamics and need to be considered when trying to analyse those data.

The project is funded by BIOMS and is part of the SFB1129 (Integrative Analysis of Pathogen Replication and Spread).

Contact: E-Mail (Last update: 11/06/2018)