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

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.

Microbial Biofilms: Human T-cell Leukemia Virus Type 1 First in Line for Viral Biofilm but Far Behind Bacterial Biofilms

“…The latter are involved in the transfer of the p8 viral protein to target cells (Van Prooyen et al, 2010), which induces LFA-1 up-regulation. This in turn reinforces cell-cell adhesion through LFA-1 interaction with ICAM-1 (Van Prooyen et al, 2010;Malbec et al, 2011;Pinto et al, 2019).…”

Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors

“…Another research group has shown IR-mediated viral activation resulting in induced transient low-level viremia in plasma of cART-treated Simian/Human Immunodeficiency Virus (SHIV)-infected macaques [44]. We have also shown that IR can induce transcription of a related retrovirus, the Human T-cell Lymphotropic Virus Type-1, and not that of cellular transcripts, showing the potential selectivity towards viral transcription [45]. Additionally, IR has clinical applications since radiotherapy is considered feasible in patients with HIV-1 and cancer [46].…”

“…IR is already used to suppress the immune system of the NOD/Shi-scid/IL-2Rgc null (NOG) mice to humanize them by the addition of human stem cells [170]. We have used this animal model extensively in the study of HIV-1 and HTLV-1 and observed no to minimal side effects to irradiation [4,45]. Therefore, the use of IR in our treatment regimen is applicable to the study of humanized mouse models.…”

Extracellular Vesicles in Viral Replication and Pathogenesis and Their Potential Role in Therapeutic Intervention

“…Due to their abilities to activate the innate and adaptive immune response, EVs can be the future pathway for the treatment of many viral infections. So far, viruses that impair their host immune response such as human T-lymphotropic virus (HTLV-1) only use their host's EVs to use viral proteins such as gp61, Tax, and HBZ to increase cell-to-cell contact and promote a potential increase in viral infection [144]. HTLV-1 EVs were found to contain a protein called TAX that is implicated with the dysregulation of the recipient cells' immune response [144,202].…”

“…So far, viruses that impair their host immune response such as human T-lymphotropic virus (HTLV-1) only use their host's EVs to use viral proteins such as gp61, Tax, and HBZ to increase cell-to-cell contact and promote a potential increase in viral infection [144]. HTLV-1 EVs were found to contain a protein called TAX that is implicated with the dysregulation of the recipient cells' immune response [144,202]. Interestingly, there are viruses that not only hijack host EVs, but also boost the production of EVs such as in ZIKA virus (ZIKV).…”