Project Details
Projekt
Elucidating the virus-host interface to inhibit transmission of Human T-cell leukemia virus type 1 (HTLV-1)
Subject Area
Virology
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 384785280
The highly oncogenic retrovirus Human T-cell leukemia virus type 1 (HTLV-1) primarily infects CD4+ T-cells in vivo and it is the cause of incurable inflammatory or neoplastic diseases after lifelong latency. The viral accessory protein p8 is proteolytically cleaved from the precursor p12 encoded by the HTLV-1 open reading frame I. p8 induces cellular protrusions and is transported through these protrusions to target cells (Van Prooyen et al., 2010). Overall, p8 enhances HTLV-1 transmission and is crucial for establishing persistent infections in vivo (Pise-Masison et al., 2014; Van Prooyen et al., 2010). We seek for a better understanding of the virus-host interface to develop strategies to interfere with p8-dependent protrusion formation, p8 transfer between cells and HTLV-1 transmission. Our previous work has shown that p8 is transferred between T-cells within minutes, depending on motility of the donor cell and on proper actin polymerization (Donhauser et al., 2018). We identified vasodilator-stimulated phosphoprotein (VASP), a regulator of actin-filament elongation, as a novel interaction partner of p8 (Donhauser et al., 2020). Knockout or shRNA-mediated repression of VASP delayed p8 transfer to target T-cells and reduced virus transmission, however, did not block it completely and had only limited impact on formation of cellular protrusions. Rather, repression of VASP impaired recruitment of p8 to the plasma membrane. Therefore, we hypothesize that additional host factors are required for p8 transfer and virus transmission, thus, proposing the existence of a “transport of p8 complex“ (TOPC). Now, we strive for the following goals:Aim 1: Elucidate composition of TOPCAim 2: Analyze mechanism of p8 transferAim 3: Interfere with p8 transfer and HTLV-1 transmissionOverall, this project will contribute to a better understanding of novel interactions of the viral protein p8 with the host cell to inhibit cellular structures required for cell-to-cell communication and HTLV-1 transmission.
DFG Programme
Research Grants
