CAREER: Viral control of cell migration in diverse host-cell types

University Of Illinois At Urbana-Champaign, Urbana IL

Investigators

Abstract

Interactions between viruses and their hosts have evolved through fierce competition over millions of years. For example, human immunodeficiency virus (HIV) forms pools of infected but dormant cells in patients. These can spontaneously reactivate after treatment ends. This project will uncover viral-host relationships that differ among different cell types within the body. Of particular interest is the mobility of infected cells. Infected T-cells that are reactivated from dormancy exhibit decreased mobility. This appears to give them the ability to more robustly invade the lymph nodes they occupy. This project will investigate whether reduced mobility is a general motif exhibited by 5 host-cell types infected with HIV. This project will help us to understand how viruses exhibit pathogenicity. It will also deepen our understanding of gene circuits and networks in different cell types. This project will also support extensive outreach activities to educate the general public, and high school, college and graduate school students regarding the mechanisms of HIV transmission and pathogenicity. Students will also have numerous opportunities to gain research experience. A novel viral-host relationship has been recently reported in which infected T-cells reactivating from latency internalize a migratory receptor, chemokine receptor 4 (CXCR4), from their cell surface. This results in HIV decreasing migration when reactivating in latently infected cells. This research will investigate the modularity of migratory control by the virus in 5 host-cell types with varying molecular backgrounds while challenged by migratory factors. The study will also elucidate how the reactivation-migration relationship depends on host cell state (cell size and cell cycle) in individual single cells. The central hypothesis to be tested is that control of migration by viral reactivation is conserved across host-cell types. The study will investigate viral control of migration in infected monocytes, monocyte derived macrophages, and macrophage polarizations M1 and M2. In addition, the reactivation-migration relationship under treatment by macrophage inhibitory factor (MIF), a secondary co-receptor of CXCR4, and its dependence on host cell size and cell cycle will be tested. The project will use live single-cell time-lapse imaging, flow cytometry, and microfluidics to accomplish the following specific aims: (1) Test if host-cell migration decreases with increasing viral reactivation in more than one cell type, (2) Investigate reactivation dependent migration challenged by combinations of migratory factors, and (3) Assess how reactivation dependent migration depends on host-cell size and cell cycle. Expected outcomes include to (i) understand modularity of viral migratory control in diverse host-cell type backgrounds, and (ii) may elucidate strategies for therapeutic agents specifically designed for cell type as well as spatial and temporal distributions throughout the body. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.