1. Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.
- Author
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Boons E, Vanstreels E, Jacquemyn M, Nogueira TC, Neggers JE, Vercruysse T, van den Oord J, Tamir S, Shacham S, Landesman Y, Snoeck R, Pannecouque C, Andrei G, and Daelemans D
- Subjects
- Acrylates chemistry, Acrylates pharmacology, Acrylates therapeutic use, Active Transport, Cell Nucleus drug effects, Animals, Apoptosis drug effects, Base Sequence, CRISPR-Cas Systems genetics, Cell Cycle Checkpoints drug effects, Cell Line, Cell Nucleus drug effects, Cell Nucleus metabolism, Female, HIV isolation & purification, Humans, Karyopherins metabolism, Mice, Nude, Molecular Sequence Data, NF-kappa B metabolism, Protein Binding drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Viral metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Reproducibility of Results, Triazoles chemistry, Triazoles pharmacology, Triazoles therapeutic use, Tumor Suppressor Protein p53 metabolism, Virus Replication drug effects, Xenograft Model Antitumor Assays, rev Gene Products, Human Immunodeficiency Virus genetics, rev Gene Products, Human Immunodeficiency Virus metabolism, Exportin 1 Protein, HIV drug effects, Karyopherins antagonists & inhibitors, Lymphoma, AIDS-Related drug therapy, Molecular Targeted Therapy, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors
- Abstract
Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.
- Published
- 2015
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