Daniel O Pinto, Sarah Al Sharif, Gifty Mensah, Maria Cowen, Pooja Khatkar, James Erickson, Heather Branscome, Thomas Lattanze, Catherine DeMarino, Farhang Alem, Ruben Magni, Weidong Zhou, Sandrine Alais, Hélène Dutartre, Nazira El-Hage, Renaud Mahieux, Lance A Liotta, Fatah Kashanchi
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引用次数: 0
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.
期刊介绍:
Retrovirology is an open access, online journal that publishes stringently peer-reviewed, high-impact articles on host-pathogen interactions, fundamental mechanisms of replication, immune defenses, animal models, and clinical science relating to retroviruses. Retroviruses are pleiotropically found in animals. Well-described examples include avian, murine and primate retroviruses.
Two human retroviruses are especially important pathogens. These are the human immunodeficiency virus, HIV, and the human T-cell leukemia virus, HTLV. HIV causes AIDS while HTLV-1 is the etiological agent for adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Retrovirology aims to cover comprehensively all aspects of human and animal retrovirus research.