The roles of the Ferlin Family in Human T-cell Leukemia Virus Type 1 Infection
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Date
2023-12-04
Access
2025-06-01
Authors
Fruge, Abigail J
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Publisher
East Carolina University
Abstract
Over 20 million people are infected with Human T-Cell Leukemia Virus type 1 (HTLV-1). HTLV-1 infection can cause diseases like aggressive Adult T-Cell leukemia and HTLV-1 associated myelopathy. These diseases are resistant to numerous forms of treatment; meaning those who develop these complications have a poor prognosis. Our laboratory has focused its research in understanding how HTLV-1 spread within the infected host to hopefully design therapeutic to suppress it.
The CD4+ T-cell are the main target of HTLV-1. HTLV-1 infection between T-cells requires a cell-to-cell contact between the infected and healthy cells. This cell-to-cell contact allows the HTLV-1 envelope glycoprotein (Env) and the other viral structural proteins to move to the cell-to-cell juncture and form a virion. Env plays a vital role in the infection in mediating the entry of the virion to the non-infected cell. Our laboratory recently reported that HBZ, a protein encoded by HTLV-1, plays a role in HTLV-1 infection. We found that HBZ activates transcription of a cellular gene called MYOF. This gene encodes myoferlin, which functions in membrane sorting and endosomal trafficking in muscle cells. HBZ activates transcription of MYOF by forming a complex at the enhancer sites inside of the MYOF gene that recruits cellular coactivator, activating transcription. We found that MYOF is abnormally overexpressed in HTLV-1 infected T-cells due to HBZ expression. We have identified MYOF as having a role in HTLV-1 infection by stabilizing the Env protein levels. Using the drug WJ460, which inhibits myoferlin function, we found that reduced expression of myoferlin in HTLV-1 infected T-cells inhibits viral infection of new cells. Reduction of myoferlin was also shown to reduce the Env expression in the cells.
My project has been to determine whether other members of the Ferlin family, otoferlin (OTO) and dysferlin (DYSF), are also expressed in HTLV-1 infected cells and have similar roles than myoferlin. Using quantitative real-time PCR, I found that DYSF mRNA is expressed in HTLV-1 infected T-cells while OTO mRNA is not. We have obtained preliminary results showing that dysferlin expression does not seem to stabilize Env level. Looking into the future of this project we hope to identify what role dysferlin plays in HTLV-1 infection.