Tyagi Richa, Li Wenxue, Parades Danelvis, Bianchet Mario A, Nath Avindra
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103, Bldg 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Retrovirology. 2017 Mar 22;14(1):21. doi: 10.1186/s12977-017-0347-4.
Human endogenous retroviruses (HERVs) are genomic sequences of retroviral origin which were believed to be integrated into germline chromosomes millions of years ago and account for nearly 8% of the human genome. Although mostly defective and inactive, some of the HERVs may be activated under certain physiological and pathological conditions. While no drugs are designed specifically targeting HERVs, there are a panel of antiretroviral drugs designed against the human immunodeficiency virus and approved by the Federal Drug Administration (FDA).
We determined if these antiretroviral drugs may also be effective in inhibiting HERVs. We constructed a plasmid with consensus HERV-K sequence for testing the effect of antiretroviral drugs on HERV-K. We first determined the effects of nucleoside and non-nucleotide reverse transcriptase (RT) inhibitors on HERV-K by product enhanced reverse transcription assay. We found that all RT inhibitors could significantly inhibit HERV-K RT activity. To determine the effects of antiretroviral drugs on HERV-K infection and viral production, we pseudotyped HERV-K with VSV-G and used the pseudotyped HERV-K virus to infect HeLa cells. HERV-K production was measured by quantitative real time polymerase chain reaction. We found that RT inhibitors Abacavir and Zidovudine, and integrase inhibitor Raltegravir could effectively block HERV-K infection and production. However, protease inhibitors were not as effective as RT and integrase inhibitors.
In summary, we identified several FDA approved antiretroviral drugs that can effectively inhibit HERV-K. These antiretrovirals may open new prospects for studying HERV-K pathophysiology and potentially for exploring treatment of diseases in which HERV-K has been implicated.
人类内源性逆转录病毒（HERVs）是逆转录病毒起源的基因组序列，据信数百万年前就整合到种系染色体中，占人类基因组近8%。尽管大多数HERVs有缺陷且无活性，但其中一些在某些生理和病理条件下可能被激活。虽然没有专门针对HERVs设计的药物，但有一组抗逆转录病毒药物是针对人类免疫缺陷病毒设计并经美国食品药品监督管理局（FDA）批准的。
我们确定了这些抗逆转录病毒药物是否也能有效抑制HERVs。我们构建了一个含有HERV-K共有序列的质粒，用于测试抗逆转录病毒药物对HERV-K的作用。我们首先通过产物增强逆转录试验确定核苷和非核苷逆转录酶（RT）抑制剂对HERV-K的作用。我们发现所有RT抑制剂都能显著抑制HERV-K的RT活性。为了确定抗逆转录病毒药物对HERV-K感染和病毒产生的影响，我们用VSV-G对HERV-K进行假型化，并使用假型化的HERV-K病毒感染HeLa细胞。通过定量实时聚合酶链反应测量HERV-K的产生。我们发现RT抑制剂阿巴卡韦和齐多夫定以及整合酶抑制剂拉替拉韦可以有效阻断HERV-K的感染和产生。然而，蛋白酶抑制剂的效果不如RT和整合酶抑制剂。
总之，我们鉴定出几种FDA批准的能有效抑制HERV-K的抗逆转录病毒药物。这些抗逆转录病毒药物可能为研究HERV-K病理生理学以及潜在探索与HERV-K相关疾病的治疗开辟新前景。
