Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.
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.
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Eline
E
Boons
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Els
E
Vanstreels
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Maarten
M
Jacquemyn
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Tatiane C
TC
Nogueira
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Jasper E
JE
Neggers
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Thomas
T
Vercruysse
KU Leuven, Department of Imaging and Pathology, Translational Cell & Tissue Research, B-3000 Leuven, Belgium.
Joost
J
van den Oord
Karyopharm Therapeutics, Newton 02459, MA, USA.
Sharon
S
Tamir
Karyopharm Therapeutics, Newton 02459, MA, USA.
Sharon
S
Shacham
Karyopharm Therapeutics, Newton 02459, MA, USA.
Yosef
Y
Landesman
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Robert
R
Snoeck
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Christophe
C
Pannecouque
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Graciela
G
Andrei
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
Dirk
D
Daelemans
D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D064113:CRISPR-Cas Systems / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016483:Lymphoma, AIDS-Related / Q000188:drug therapy*; D008819:Mice, Nude; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
D000179:Acrylates; D028884:Karyopherins; D016328:NF-kappa B; D012333:RNA, Messenger; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D054321:rev Gene Products, Human Immunodeficiency Virus; D000097606:Exportin 1 Protein; C576639:KPT-185
AIDS-related lymphoma; CRM1; Exportin-1; HIV; Primary effusion lymphoma; Small-molecule inhibitors; XPO1