Tools

LEADER 04653cam 2200577 i 4500

001 on1201526253;

003 OCoLC;

005 20250721152916.0;

006 m o d ;

007 cr unu||||||||;

008 201026s2020 ncua obm 000 0 eng d;

035 a| (Sirsi) o1201526253;

035 a| (OCoLC)1201526253;

049 a| EREE;

096 a| WC 502;

100 1 a| Norton, Christopher,e| author.=| ^A1183734;

245 10 a| Targeting exportin-1 to inhibit HTLV-1 infection /c| by Christopher Norton.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2020.;

300 a| 1 online resource (73 pages) :b| illustrations (some color).;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text file;

347 b| PDF;

347 c| 1.630 MB;

490 1 a| ECU Brody School of Medicine thesis;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Biomedical Sciencec| East Carolina Universityd| 2020;

502 a| Presented to the Faculty of the Biomedical Sciences Program;

500 a| Advisor: Isabelle Lemasson;

500 a| Title from PDF t.p. (viewed May 14, 2025).;

520 3 a| Human T-cell Leukemia Virus Type-1 (HTLV-1) is a complex human retrovirus that infects around 20 million people globally. Transmission of this retrovirus occurs by sexual intercourse, contaminated blood, and from mother to child by breastfeeding. While HTLV-1 is asymptomatic in most of the infected hosts, around 5% will develop an HTLV-1 associated disease such as Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). ATLL is a malignant and aggressive form of cancer that occurs in CD4+ T-cells. HAM/TSP is a neurological disorder that is believed to be caused by the infiltration of HTLV-1 infected cells into the central nervous system leading to axon demyelination. There are no effective treatments or cures for HTLV-1-associated diseases, and there is no prophylactic vaccine. Furthermore, there is no anti-retroviral treatment that has yet been successful to inhibit HTLV-1 infection in clinical studies. We focused our research on the protein exportin-1 (XPO-1). XPO-1 mediates the nuclear export of messenger RNA (mRNA) for the purpose of cell survival, proliferation, and metastasis. Interestingly, XPO-1 has been shown to facilitate the nuclear export of certain HTLV-1 mRNA necessary for virion formation, such as Gag/Pol and Env mRNA. Recently, some compounds known as Selective Inhibitor of Nuclear Export (SINE) have been designed to bind to a cysteine residue of XPO-1 to prevent the binding of nuclear cargo. We used one of these SINE molecules, KPT-185, to determine its efficiency in inhibiting HTLV-1 infection. Our results revealed that treatment of HTLV-1 cells derived from ATLL patients treated with KPT-185 did not lead to cell death. However, KPT-185 was successful in inhibiting the export of the Gag/Pol mRNA leading to reduced levels of Gag protein in the cells. In addition, we also find that KPT-185 reduced the level of the envelope protein that coat HTLV-1 virions. In correlation with these observations, we found less virions to be released and a significant reduction of HTLV-1 capability to infect other CD4+ T-cells. Therefore, our observation that KPT-185 inhibits HTLV-1 infection indicate that this compound could be an effective form of prevention of HTLV-1 spread and the development of associated diseases.;

504 a| Includes bibliographical references.;

650 2 a| Human T-lymphotropic virus 1.=| ^A1037506;

650 2 a| HTLV-I Infections.=| ^A956924;

655 7 a| dissertations.2| aat0| (CStmoGRI)aatgf300028029;

655 7 a| Academic theses.2| fast0| (OCoLC)fst01726453;

655 7 a| Academic theses.2| lcgft;

655 7 a| Thèses et écrits académiques.2| rvmgf0| (CaQQLa)RVMGF-000001173;

700 1 a| Lemasson, Isabelle,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Biomedical Science.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 u| http://hdl.handle.net/10342/8730z| Access via ScholarShip;

949 o| wjh;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 5524886;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5524886-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 10/26/2020x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5524886-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 10/26/2020x| ETDz| HERESOURCE;

Targeting exportin-1 to inhibit HTLV-1 infection / by Christopher Norton.

Author/creator	Norton, Christopher author.
Other author	Lemasson, Isabelle, degree supervisor.
Other author	East Carolina University. Department of Biomedical Science.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2020.
Description	1 online resource (73 pages) : illustrations (some color).
Supplemental Content	Access via ScholarShip
Subjects	Human T-lymphotropic virus 1. HTLV-I Infections.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
Summary	Human T-cell Leukemia Virus Type-1 (HTLV-1) is a complex human retrovirus that infects around 20 million people globally. Transmission of this retrovirus occurs by sexual intercourse, contaminated blood, and from mother to child by breastfeeding. While HTLV-1 is asymptomatic in most of the infected hosts, around 5% will develop an HTLV-1 associated disease such as Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). ATLL is a malignant and aggressive form of cancer that occurs in CD4+ T-cells. HAM/TSP is a neurological disorder that is believed to be caused by the infiltration of HTLV-1 infected cells into the central nervous system leading to axon demyelination. There are no effective treatments or cures for HTLV-1-associated diseases, and there is no prophylactic vaccine. Furthermore, there is no anti-retroviral treatment that has yet been successful to inhibit HTLV-1 infection in clinical studies. We focused our research on the protein exportin-1 (XPO-1). XPO-1 mediates the nuclear export of messenger RNA (mRNA) for the purpose of cell survival, proliferation, and metastasis. Interestingly, XPO-1 has been shown to facilitate the nuclear export of certain HTLV-1 mRNA necessary for virion formation, such as Gag/Pol and Env mRNA. Recently, some compounds known as Selective Inhibitor of Nuclear Export (SINE) have been designed to bind to a cysteine residue of XPO-1 to prevent the binding of nuclear cargo. We used one of these SINE molecules, KPT-185, to determine its efficiency in inhibiting HTLV-1 infection. Our results revealed that treatment of HTLV-1 cells derived from ATLL patients treated with KPT-185 did not lead to cell death. However, KPT-185 was successful in inhibiting the export of the Gag/Pol mRNA leading to reduced levels of Gag protein in the cells. In addition, we also find that KPT-185 reduced the level of the envelope protein that coat HTLV-1 virions. In correlation with these observations, we found less virions to be released and a significant reduction of HTLV-1 capability to infect other CD4+ T-cells. Therefore, our observation that KPT-185 inhibits HTLV-1 infection indicate that this compound could be an effective form of prevention of HTLV-1 spread and the development of associated diseases.
General note	Advisor: Isabelle Lemasson
General note	Title from PDF t.p. (viewed May 14, 2025).
Dissertation note	Biomedical Science East Carolina University 2020
Dissertation note	Presented to the Faculty of the Biomedical Sciences Program
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.
Genre/form	dissertations.
Genre/form	Academic theses.
Genre/form	Academic theses.
Genre/form	Thèses et écrits académiques.

Targeting exportin-1 to inhibit HTLV-1 infection / by Christopher Norton.

Click here for more information about this title