E. Jaworski, A. Narayanan, R. V. Duyne, S. Shabbeer-Meyering, S. Iordanskiy, M. Saifuddin, Ravi Das, P. V. Afonso, G. C. Sampey, M. Chung, A. Popratiloff, B. Shrestha, M. Sehgal, P. Jain, A. Vertes, R. Mahieux, and F. Kashanchi
Journal of Biological Chemistry, 2014, June
DOI: 110.1074/jbc.M114.549659 | Impact factor (2012):
Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The HTLV-1 transactivator protein Tax controls many critical cellular pathways including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Recently, extracellular vesicles called exosomes have been shown to play critical roles during pathogenic viral infections as delivery vehicles for host and viral components including proteins, mRNA and miRNA. We hypothesized that exosomes derived from HTLV-1 infected cells contain unique host and viral proteins that may contribute to pathogenesis. We found that exosomes derived from infected cells contained Tax protein and pro-inflammatory mediators, as well as viral mRNA transcripts including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1 infected Tax-expressing cells contributed to enhanced survival of target cells when treated with Fas antibody. This survival was cFLIP dependent and Tax clearly showed induction of NF-kB in cells. Finally, IL-2 dependent CTLL-2 cells that received Tax containing exosomes were protected from apoptosis through activation of AKT. Similar experiments also showed protection of PBMCs in 15 day cultures in the absence of PHA/IL-2. Surviving cells contained more phosphorylated Rb consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells.