1. Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread
- Author
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Ruben Magni, Daniel O. Pinto, Heather Branscome, James Erickson, Hélène Dutartre, Pooja Khatkar, Gifty A. Mensah, Sandrine Alais, Thomas Lattanze, Fatah Kashanchi, Weidong Zhou, Renaud Mahieux, Lance A. Liotta, Nazira El-Hage, Maria Cowen, Catherine DeMarino, Sarah Al Sharif, and Farhang Alem
- Subjects
Proteomics ,lcsh:Immunologic diseases. Allergy ,Cell signaling ,THP-1 Cells ,Spleen ,Mice, Transgenic ,Cell Communication ,Biology ,Virus ,03 medical and health sciences ,Extracellular Vesicles ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Virology ,Tropical spastic paraparesis ,medicine ,Animals ,Humans ,THP1 cell line ,030304 developmental biology ,0303 health sciences ,Human T-lymphotropic virus 1 ,U937 cell ,Research ,Endothelial Cells ,Dendritic cell ,U937 Cells ,medicine.disease ,HTLV-I Infections ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Humanized mouse ,Cytokines ,Female ,lcsh:RC581-607 - Abstract
Background The Human T-cell Lymphotropic Virus Type-1 (HTLV-1) is a blood-borne pathogen and etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 has currently infected up to 10 million globally with highly endemic areas in Japan, Africa, the Caribbean and South America. We have previously shown that Extracellular Vesicles (EVs) enhance HTLV-1 transmission by promoting cell–cell contact. Results Here, we separated EVs into subpopulations using differential ultracentrifugation (DUC) at speeds of 2 k (2000×g), 10 k (10,000×g), and 100 k (100,000×g) from infected cell supernatants. Proteomic analysis revealed that EVs contain the highest viral/host protein abundance in the 2 k subpopulation (2 k > 10 k > 100 k). The 2 k and 10 k populations contained viral proteins (i.e., p19 and Tax), and autophagy proteins (i.e., LC3 and p62) suggesting presence of autophagosomes as well as core histones. Interestingly, the use of 2 k EVs in an angiogenesis assay (mesenchymal stem cells + endothelial cells) caused deterioration of vascular-like-tubules. Cells commonly associated with the neurovascular unit (i.e., astrocytes, neurons, and macrophages) in the blood–brain barrier (BBB) showed that HTLV-1 EVs may induce expression of cytokines involved in migration (i.e., IL-8; 100 k > 2 k > 10 k) from astrocytes and monocyte-derived macrophages (i.e., IL-8; 2 k > 10 k). Finally, we found that EVs were able to promote cell–cell contact and viral transmission in monocytic cell-derived dendritic cell. The EVs from both 2 k and 10 k increased HTLV-1 spread in a humanized mouse model, as evidenced by an increase in proviral DNA and RNA in the Blood, Lymph Node, and Spleen. Conclusions Altogether, these data suggest that various EV subpopulations induce cytokine expression, tissue damage, and viral spread.
- Published
- 2021