Abstract
The human T-cell leukemia virus type 1 (HTLV-1) is highly dependent on cell-to-cell interaction for transmission and productive infection. Cell-to-cell interactions through the virological synapse, biofilm-like structures and cellular conduits have been reported, but the relative contribution of each mechanism on HTLV-1 transmission still remains vastly unknown. The HTLV-1 protein p8 has been found to increase viral transmission and cellular conduits. Here we show that HTLV-1 expressing cells are interconnected by tunneling nanotubes (TNTs) defined as thin structures containing F-actin and lack of tubulin connecting two cells. TNTs connected HTLV-1 expressing cells and uninfected T-cells and monocytes and the viral proteins Tax and Gag localized to these TNTs. The HTLV-1 expressing protein p8 was found to induce TNT formation. Treatment of MT-2 cells with the nucleoside analog cytarabine (cytosine arabinoside, AraC) reduced number of TNTs and furthermore reduced TNT formation induced by the p8 protein. Intercellular transmission of HTLV-1 through TNTs provides a means of escape from recognition by the immune system. Cytarabine could represent a novel anti-HTLV-1 drug interfering with viral transmission.
Highlights
Surface of human the human T-cell leukemia virus type 1 (HTLV-1)-negative cell lines Jurkat (T-cells) leukemia virus type 1 (HTLV-1) infected cell lines[32]
For long distance cell-to-cell interactions we previously reported viral transmission in T-cells by cellular conduits, a process enhanced by the HTLV-1 encoded protein p833,34
By sequencing of orf-I in the HTLV-1 infected cell lines included in this study we found that the MT-2 cells, demonstrating the highest amount of tunneling nanotubes (TNTs), contained the orf-I isoform N26, earlier demonstrated to express mostly the p8 protein[36]
Summary
Surface of HTLV-1 infected cell lines[32]. The HTLV-1 particles are concentrated and protected by the biofilms and transmitted to the target cell[32]. For long distance cell-to-cell interactions we previously reported viral transmission in T-cells by cellular conduits, a process enhanced by the HTLV-1 encoded protein p833,34. We further examined long-distance cell-to-cell interactions utilized by HTLV-1 expressing T-cells and found that these infected cells form tunneling nanotubes (TNTs), often containing the viral proteins Tax and Gag, between T-cells as well as monocytes. In MT-2 cells, cytarabine reduced expression of Tax, Gag and viral production and caused a decrease in viral transmission from MT-2 cells as well as primary HTLV-1 infected CD4+ cells to uninfected cells. By sequencing of orf-I in the HTLV-1 infected cell lines included in this study we found that the MT-2 cells, demonstrating the highest amount of TNTs, contained the orf-I isoform N26, earlier demonstrated to express mostly the p8 protein[36]. Our work shows that cytarabine could have possible therapeutic effects to reduce HTLV-1 transmission by reduced communication of HTLV-1 infected cells with uninfected cells
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