Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.
Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.
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DOI：
10.1016/j.ebiom.2015.07.041
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发表时间：
2015-09
期刊：
影响因子：
11.1
通讯作者：
Daelemans D
中科院分区：
文献类型：
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作者：
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;Daelemans D
感染艾滋病毒最终会导致严重的免疫缺陷，导致癌症发病率增加。例如，原发性渗出性淋巴瘤(PEL)是一种预后非常差的侵袭性非霍奇金淋巴瘤，通常影响免疫缺陷晚期的艾滋病毒感染者。在这里，我们报告了针对两种疾病中常见的单一过程的双重抗HIV和抗PEL效果。临床阶段口服生物可用小分子抑制剂(SINE)可抑制Exportin-1(XPO1)介导的核转运，从而阻止含有内含子的晚期HIV RNA物种的核输出，从而有效地抑制病毒复制。相反，在表达突变C528S XPO1的CRISPR-Cas9基因组编辑细胞中，病毒复制在治疗后没有受到影响，清楚地表明了抗XPO1的作用机制。同时，Sine可引起P53抑癌蛋白的核内积聚，抑制核转录因子-κB的活性，导致细胞周期停滞，有效地诱导细胞凋亡。在体内，口服给药抑制了移植小鼠PEL肿瘤的生长。我们的发现为抑制XPO1作为HIV和PEL的抗逆转录病毒和抗肿瘤联合治疗的创新策略提供了强有力的理由，并为其他艾滋病相关癌症和潜在的其他病毒相关恶性肿瘤的治疗提供了前景。选择性抑制XPO1可抑制HIV复制并诱导PEL细胞凋亡。临床阶段口服生物可用XPO1抑制剂显示出强大的抗HIV和抗PEL活性。这项研究验证了XPO1抑制作为治疗PEL的一种策略，特别是在HIV感染的情况下。感染人类免疫缺陷病毒(HIV)会损害人体的免疫系统，使感染者容易患上包括癌症在内的其他疾病。一些形式的癌症通常发生在艾滋病患者身上，例如侵袭性很强、通常最致命的原发渗出性淋巴瘤(PEL)。目前还没有针对PEL的标准治疗方法，但抗HIV药物的使用与更好的预后相关。在这里，我们在临床前试验中表明，核出口的抑制剂既能抑制HIV复制，也能抑制PEL进展。这些发现为进一步评估这些抑制剂作为艾滋病毒/淋巴瘤双重治疗策略提供了理论基础。
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. Selective inhibition of XPO1 suppresses the replication of HIV and induces apoptosis in PEL cells. Clinical stage orally bioavailable XPO1 inhibitors display potent anti-HIV and anti-PEL activity. This study validates XPO1 inhibition as a treatment strategy for PEL, especially in the setting of HIV-infection. Infection with human immunodeficiency virus (HIV) compromises the body's immune system leaving infected individuals vulnerable to other pathologies including cancer. Some forms of cancer typically develop in AIDS patients, as for example the very aggressive and most often deadly primary effusion lymphoma (PEL). There is currently no standard treatment for PEL but the use of anti-HIV drugs is associated with better prognosis. Here we show in preclinical tests that inhibitors of nuclear export suppress both HIV replication as well as PEL progression. These findings provide a rationale for further evaluating these inhibitors as treatment strategy for dual HIV/lymphoma therapy.