Experimental and computational analyses reveal that environmental restrictions shape HIV-1 spread in 3D cultures
2019
Authors: Imle A, Kumberger P, Schnellbächer ND, Fehr J, Carillo-Bustamante P, Ales J, Schmidt P, Ritter C, Godinez WJ, Müller B, Rohr K, Hamprecht FA, Schwarz US, Graw F, Fackler OT
CellNetworks People: Fackler Oliver, Hamprecht Fred, Müller Barbara, Rohr Karl, Schwarz Ulrich
Journal: Nat Commun. 2019 May 13;10:2144. doi.org/10.1038/s41467-019-09879-3

Pathogens face varying microenvironments in vivo, but suitable experimental systems and analysis tools to dissect how three-dimensional (3D) tissue environments impact pathogen spread are lacking. Here we develop an Integrative method to Study Pathogen spread by Experiment and Computation within Tissue-like 3D cultures (INSPECT-3D), combining quantification of pathogen replication with imaging to study single-cell and cell population dynamics. We apply INSPECT-3D to analyze HIV-1 spread between primary human CD4 T-lymphocytes using collagen as tissue-like 3D-scaffold. Measurements of virus replication, infectivity, diffusion, cellular motility and interactions are combined by mathematical analyses into an integrated spatial infection model to estimate parameters governing HIV-1 spread. This reveals that environmental restrictions limit infection by cell-free virions but promote cell-associated HIV-1 transmission. Experimental validation identifies cell motility and density as essential determinants of efficacy and mode of HIV-1 spread in 3D. INSPECT-3D represents an adaptable method for quantitative time-resolved analyses of 3D pathogen spread.