Contreras-Galindo Rafael, Dube Derek, Fujinaga Koh, Kaplan Mark H, Markovitz David M
Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, USA
Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, USA.
J Virol. 2017 Nov 14;91(23). doi: 10.1128/JVI.01309-17. Print 2017 Dec 1.
Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants into the human germ line and are transcriptionally active. In HIV-1 infection and cancer, HK2 genes produce retroviral particles that appear to be infectious, yet the replication capacity of these viruses and potential pathogenicity has been difficult to ascertain. In this report, we screened the efficacy of commercially available reverse transcriptase inhibitors (RTIs) at inhibiting the enzymatic activity of HK2 RT and HK2 genomic replication. Interestingly, only one provirus, K103, was found to encode a functional RT among those examined. Several nucleoside analogue RTIs (NRTIs) blocked K103 RT activity and consistently inhibited the replication of HK2 genomes. The NRTIs zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), and the nucleotide RTI inhibitor tenofovir (TDF), show efficacy in blocking K103 RT. HIV-1-specific nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (IIs) did not affect HK2, except for the NNRTI etravirine (ETV). The inhibition of HK2 infectivity by NRTIs appears to take place at either the reverse transcription step of the viral genome prior to HK2 viral particle formation and/or in the infected cells. Inhibition of HK2 by these drugs will be useful in suppressing HK2 infectivity if these viruses prove to be pathogenic in cancer, neurological disorders, or other diseases associated with HK2. The present studies also elucidate a key aspect of the life cycle of HK2, specifically addressing how they do, and/or did, replicate. Endogenous retroviruses are relics of ancestral virus infections in the human genome. The most recent of these infections was caused by HK2. While HK2 often remains silent in the genome, this group of viruses is activated in HIV-1-infected and cancer cells. Recent evidence suggests that these viruses are infectious, and the potential exists for HK2 to contribute to disease. We show that HK2, and specifically the enzyme that mediates virus replication, can be inhibited by a panel of drugs that are commercially available. We show that several drugs block HK2 with different efficacies. The inhibition of HK2 replication by antiretroviral drugs appears to occur in the virus itself as well as after infection of cells. Therefore, these drugs might prove to be an effective treatment by suppressing HK2 infectivity in diseases where these viruses have been implicated, such as cancer and neurological syndromes.
人类内源性逆转录病毒（HERV）占人类基因组的8%。HERV-K（HML-2）（HK2）家族包含的前病毒是人类种系中最新进入的，且具有转录活性。在HIV-1感染和癌症中，HK2基因产生似乎具有传染性的逆转录病毒颗粒，然而这些病毒的复制能力和潜在致病性一直难以确定。在本报告中，我们筛选了市售逆转录酶抑制剂（RTI）抑制HK2逆转录酶（RT）酶活性和HK2基因组复制的效果。有趣的是，在所检测的前病毒中，仅发现一种K103编码功能性RT。几种核苷类似物RTI（NRTI）阻断了K103 RT活性，并持续抑制HK2基因组的复制。NRTI齐多夫定（AZT）、司他夫定（d4T）、去羟肌苷（ddI）和拉米夫定（3TC），以及核苷酸RTI抑制剂替诺福韦（TDF），在阻断K103 RT方面显示出效果。HIV-1特异性非核苷RTI（NNRTI）、蛋白酶抑制剂（PI）和整合酶抑制剂（II）对HK2没有影响，除了NNRTI依曲韦林（ETV）。NRTI对HK2感染性的抑制似乎发生在HK2病毒颗粒形成之前病毒基因组的逆转录步骤和/或感染细胞中。如果这些病毒在癌症、神经疾病或与HK2相关的其他疾病中被证明具有致病性，那么这些药物对HK2感染性的抑制将有助于抑制HK2的感染性。本研究还阐明了HK2生命周期的一个关键方面，特别是阐述了它们如何进行和/或曾经进行复制。内源性逆转录病毒是人类基因组中祖先病毒感染的遗迹。这些感染中最新的是由HK2引起的。虽然HK2在基因组中通常保持沉默，但这组病毒在HIV-1感染的细胞和癌细胞中被激活。最近的证据表明这些病毒具有传染性，并且HK2有导致疾病的可能性。我们表明HK2，特别是介导病毒复制的酶，可以被一组市售药物抑制。我们表明几种药物以不同的效果阻断HK2。抗逆转录病毒药物对HK2复制的抑制似乎发生在病毒本身以及细胞感染后。因此，在这些病毒涉及相关的疾病如癌症和神经综合征中，这些药物可能通过抑制HK2感染性而被证明是一种有效的治疗方法。
