Targeting Exportin-1 to Inhibit HTLV-1 Infection

Abstract

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.