Advisor | Lemasson, Isabelle | |
Author | Fazio-Kroll, Ana Laura | |
Date Accessioned | 2017-06-01T12:14:43Z | |
Date Available | 2020-01-23T09:01:57Z | |
Date Created | 2017-05 | |
Date of Issue | 2017-04-28 | |
xmlui.metadata.dc.date.submitted | May 2017 | |
Identifier (URI) | http://hdl.handle.net/10342/6200 | |
Description | The complex retrovirus Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of several diseases, including Adult T cell leukemia (ATL), a fatal hematological malignancy that affects mainly CD4+ T-cells. Freshly isolated ATL and HTLV-1 infected cells aggregate spontaneously in vitro. We have observed this same phenotype in T-cells exclusively expressing one of the viral proteins called HTLV-1 basic leucine zipper factor (HBZ). The hbz gene is uniquely encoded by the complementary strand of the HTLV-1 provirus and, in contrast to other HTLV-1 proteins, is constitutively expressed in ATL and HTLV-1-infected cells. High levels of aggregation in ATL cells have been correlated to an upregulation of the intercellular adhesion molecule-1 (ICAM-1). This protein is usually activated after T-cell stimulation and plays an important role in forming and stabilizing the immunological synapse. Interestingly, we found that cells expressing HBZ have an increase in ICAM-1 mRNA, which correlates with an increase in ICAM-1 at the cell surface. We confirmed by luciferase assay that HBZ expression stimulates ICAM-1 transcription. We found that blocking antibodies or peptides against ICAM-1 and its ligand, lymphocyte function-associated antigen 1 (LFA-1), dissociate the aggregates formed by HBZ-expressing cells, suggesting that ICAM-1 overexpression by HBZ mediates T-cell aggregation through interaction with LFA-1. Increased ICAM-1 expression at the cell surface is crucial for the formation of cell-to-cell contacts and efficient HTLV-1 transmission. To determine whether overexpression of ICAM-1 by HBZ plays a role in viral spread, we performed infection assays using a single-cycle, replication dependent reporter system. Interestingly, we found that HBZ expression significantly enhances HTLV-1 transmission. We confirmed that this effect involves the presence of LFA-1 on target cells. In addition, blocking the ICAM-1/LFA-1 interaction with an ICAM-1 antibody significantly reduced viral transmission. Therefore, ICAM-1 overexpression by HBZ plays a role in mediating viral transmission in our assays. A better understanding of the mechanisms used by HBZ to upregulate ICAM-1, induce cell-to-cell contact, and enhance virus transmission is important for future efforts to limit viral spread and prevent diseases in HTLV-1-infected individuals. | |
Mimetype | application/pdf | |
Language | en | |
Publisher | East Carolina University | |
Medical Subject Headings | Human T-lymphotropic virus 1 | |
Medical Subject Headings | Protein HBZ | |
Medical Subject Headings | Viral transmission | |
Title | NOVEL ROLE OF HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 ENCODED PROTEIN HBZ IN VIRAL TRANSMISSION THROUGH CELL-TO-CELL CONTACT | |
Type | Doctoral Dissertation | |
xmlui.metadata.dc.date.updated | 2017-05-30T19:38:00Z | |
Department | Microbiology and Immunology | |
xmlui.metadata.dc.degree.name | Ph.D. | |
xmlui.metadata.dc.degree.level | Doctoral | |
xmlui.metadata.dc.degree.discipline | PHD-Microbiology & Immunology | |
xmlui.metadata.dc.degree.grantor | East Carolina University | |
xmlui.metadata.dc.degree.department | Microbiology and Immunology | |
xmlui.metadata.dc.access.option | Open Access | |
xmlui.metadata.dc.embargo.lift | 2019-05-01 | |
xmlui.metadata.dc.type.material | text | |