Abstract
Human T-cell leukemia virus-1 (HTLV-1) is a neglected and incurable retrovirus estimated to infect 5 to 10 million worldwide. Specific indigenous Australian populations report infection rates of more than 40%, suggesting a potential evolution of the virus with global implications. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL), and a neurological disease named 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 Extracellular Vesicles (EVs) ubiquitously produced by cells may be used by HTLV-1 to transport viral proteins and RNA, and elicit adverse effects on recipient uninfected cells. The viral proteins Tax and HBZ are involved in disease progression and impairment of autophagy in infected cells. Here, we show that activation of HTLV-1 via ionizing radiation (IR) causes a significant increase of intracellular Tax, but not EV-associated Tax. Also, lower density EVs from HTLV-1-infected cells, separated by an Iodixanol density gradient, are positive for gp61+++/Tax+++/HBZ+ proteins (HTLV-1 EVs). We found that HTLV-1 EVs are not infectious when tested in multiple cell lines. However, these EVs promote cell-to-cell contact of uninfected cells, a phenotype which was enhanced with IR, potentially promoting viral spread. We treated humanized NOG mice with HTLV-1 EVs prior to infection and observed an increase in viral RNA synthesis in mice compared to control (EVs from uninfected cells). Proviral DNA levels were also quantified in blood, lung, spleen, liver, and brain post-treatment with HTLV-1 EVs, and we observed a consistent increase in viral DNA levels across all tissues, especially the brain. Finally, we show direct implications of EVs in viral spread and disease progression and suggest a two-step model of infection including the release of EVs from donor cells and recruitment of recipient cells as well as an increase in recipient cell-to-cell contact promoting viral spread.
Highlights
Human T-cell leukemia virus-1 (HTLV-1) is a neglected bloodborne pathogen that indiscriminately infects people of all ages around the world (Gallo, 2011; Gallo et al, 2016; Tagaya and Gallo, 2017; Martin et al, 2018)
We recently found that HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient cerebral spinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) consistently express Tax associated with Extracellular Vesicles (EVs) that may trigger inflammatory responses known to cause neurodegeneration (Anderson M.R. et al, 2018)
HTLV-1-infected HUT102 cells were treated with ionizing radiation (IR) (10 Gy) and incubated for 5 days to allow for maximal EV release, as described previously for HTLV-1 and other viruses (Narayanan et al, 2013; Jaworski et al, 2014a,b; Sampey et al, 2016; Barclay et al, 2017b; Anderson M.R. et al, 2018)
Summary
Human T-cell leukemia virus-1 (HTLV-1) is a neglected bloodborne pathogen that indiscriminately infects people of all ages around the world (Gallo, 2011; Gallo et al, 2016; Tagaya and Gallo, 2017; Martin et al, 2018). 5–10 million people worldwide carry HTLV-1, this estimate does not include epidemiological data from highly populated regions, such as China, India, Maghreb, and East Africa, and very limited epidemiological data from Africa where the virus is endemic. Reports of high HTLV-1 infection rates, of 40% and above, in remote Australian populations are cause of global concern (Einsiedel et al, 2016, 2018). HTLV-1infected individuals remain asymptomatic and possibly unaware of their infection status (Hinuma et al, 1981; Gonçalves et al, 2010; Gessain and Cassar, 2012), which is especially concerning since a significant route of transmission occurs from mother to child via breastfeeding (Fujino and Nagata, 2000; Einsiedel et al, 2016). It is likely that, due to a lack of universal screening recommendations, more people globally are at risk of infection via sexual contact, blood transfusions and organ transplants (Gallo et al, 2016; de Morais et al, 2017; Caswell et al, 2019)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
