HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact
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 adul...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.02147/full |
| _version_ | 1811220619923030016 |
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| author | Daniel O. Pinto Catherine DeMarino Michelle L. Pleet Maria Cowen Heather Branscome Sarah Al Sharif Jennifer Jones Helene Dutartre Benjamin Lepene Lance A. Liotta Renaud Mahieux Fatah Kashanchi |
| author_facet | Daniel O. Pinto Catherine DeMarino Michelle L. Pleet Maria Cowen Heather Branscome Sarah Al Sharif Jennifer Jones Helene Dutartre Benjamin Lepene Lance A. Liotta Renaud Mahieux Fatah Kashanchi |
| author_sort | Daniel O. Pinto |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T07:45:16Z |
| format | Article |
| id | doaj.art-af288fdff8204397bc151f3b2423b3f2 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-12T07:45:16Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-af288fdff8204397bc151f3b2423b3f22022-12-22T03:41:43ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-09-011010.3389/fmicb.2019.02147453810HTLV-1 Extracellular Vesicles Promote Cell-to-Cell ContactDaniel O. Pinto0Catherine DeMarino1Michelle L. Pleet2Maria Cowen3Heather Branscome4Sarah Al Sharif5Jennifer Jones6Helene Dutartre7Benjamin Lepene8Lance A. Liotta9Renaud Mahieux10Fatah Kashanchi11Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesLaboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesLaboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesLaboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesLaboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesLaboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesVaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesInternational Center for Research in Infectiology, Retroviral Oncogenesis Laboratory, INSERM U1111-Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université de Lyon, Fondation pour la Recherche Médicale, Labex Ecofect, Lyon, FranceCeres Nanosciences, Inc., Manassas, VA, United StatesCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United StatesInternational Center for Research in Infectiology, Retroviral Oncogenesis Laboratory, INSERM U1111-Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université de Lyon, Fondation pour la Recherche Médicale, Labex Ecofect, Lyon, FranceLaboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United StatesHuman 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.https://www.frontiersin.org/article/10.3389/fmicb.2019.02147/fullHTLV-1extracellular vesicleviral spreadtaxcell-to-cell contactinfection |
| spellingShingle | Daniel O. Pinto Catherine DeMarino Michelle L. Pleet Maria Cowen Heather Branscome Sarah Al Sharif Jennifer Jones Helene Dutartre Benjamin Lepene Lance A. Liotta Renaud Mahieux Fatah Kashanchi HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact Frontiers in Microbiology HTLV-1 extracellular vesicle viral spread tax cell-to-cell contact infection |
| title | HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact |
| title_full | HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact |
| title_fullStr | HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact |
| title_full_unstemmed | HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact |
| title_short | HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact |
| title_sort | htlv 1 extracellular vesicles promote cell to cell contact |
| topic | HTLV-1 extracellular vesicle viral spread tax cell-to-cell contact infection |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.02147/full |
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