HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact

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Human T-cell leukemia virus-1 (HTLV-1) is a neglected and incurable retrovirus estimated to infect 5 to 10 million A) B) worldwide. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL), and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Even though HTLV-1 transmission primarily occurs from cell-to-cell, there is still a gap of

knowledge regarding the mechanisms of viral spread and disease progression. We have recently shown that the small membrane structures, known as Extracellular Vesicles (EVs), may contain the HTLV-1 protein, Tax. We have also shown that EVs isolated from HTLV-1 positive PBMC (12/20) and CSF (25/36) patient samples may be associated to Tax and elicit cytotoxic T-cell lysis, evidence of functional and clinical roles of EVs in HTLV-1 infection. Here, we show that ionizing radiation (IR) caused an increase in both intracellular Tax protein and HTLV-1 specific viral transcription (i.e., env, tax, and hbz). Viral activation was also accompanied by an increase in EV release from HTLV-1 infected cells. HTLV-1 EVs separated by a density gradient show that lower density EVs are positive for gp61+++/Tax+++/HBZ+ proteins. We found that HTLV-1 EVs co-localize with recipient T-cells and caused increased cell-to-cell contact, resulting in increased viral transcription after addition of infected donor cells in-vitro and in-vivo. Finally, we treated a panel of neutralizing antibodies and found that α-CD45 was able to prevent increased cell-to-cell contact in recipient T-cells. In conclusion, we show direct implications of EVs

in HTLV-1 infection and propose a two-step model of infection which includes EV release from donor cells and recruitment of recipient cells, followed by an increase in recipient cell-to-cell contact and enhanced viral spread.


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