Extracellular Vesicle Subpopulations From HTLV-1 Infected Cells Induce Differential Effects in Recipient Cells


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Human T-cell Leukemia Virus Type 1 (HTLV-1) is the causative agent of Adult T-Cell Leukemia/Lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Extracellular vesicles (EVs)—membrane-bound vesicles excreted by cells into the microenvironment which play an extensive role in cell-to-cell communication—have been implicated in contributing to these two conditions by carrying cellular materials from donor cells to recipient cells. Our lab has previously shown that EVs from ATLL cells contain viral protein and mRNA and promote cell-to-cell contact when placed on uninfected recipient CD4+ T-cells, enhancing HTLV-1 infectivity. Another recent paper involving ATLL EVs resulted in mesenchymal stem cell proliferation and was attributed to helping aid in leukemic progression. Because ATLL is a leukocytic cancer, ATLL EVs have the potential to interact with any cells that blood or biofluids interact with. However, a gap in knowledge exists relating to how ATLL EVs interact with differentiated non-leukocytes. In addition, many of the conclusions made about the effects of cancer “extracellular vesicles” look at a small subpopulation within the total EV population, and have not been generalized. Therefore, in this study, we sought to better understand the different impacts of individual ATLL EV subpopulations upon non-leukocytes. We found that differential ultracentrifugation subpopulations (2K, 10K, 100K, 167K (4hr) and 167K (16hr)) of HuT102 EVs contained different distributions of viral proteins, viral mRNA, and vesicle-associated proteins. We saw that HeLa cells treated with EV subpopulations had no change in cell viability but had preservation of normal cell morphology post-confluency and had different patterns of anchorage-dependent proliferation. Furthermore, we found that less-dense EV subpopulations 100K and 167K (16hr) helped promote anchorage-independent proliferation. Collectively, our data suggests that there may be a correlation between subpopulations with high amounts of vesicle markers and anchorage-dependent proliferation, while subpopulations with low amounts of viral markers may promote anchorage-independent proliferation. These findings prompt further research into how the contents of each ATLL subpopulation affect recipient cell proliferation and whether these recipient cells are pushed towards cancer development.