Taura Manabu, Kudo Eriko, Kariya Ryusho, Goto Hiroki, Matsuda Kouki, Hattori Shinichiro, Vaeteewoottacharn Kulthida, McDonald Fiona, Suico Mary Ann, Shuto Tsuyoshi, Kai Hirofumi, Okada Seiji
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
Department of Physiology, University of Otago, Dunedin, New Zealand.
J Virol. 2015 Mar;89(5):2643-58. doi: 10.1128/JVI.03105-14. Epub 2014 Dec 17.
The transcription factor NF-κB is important for HIV-1 transcription initiation in primary HIV-1 infection and reactivation in latently HIV-1-infected cells. However, comparative analysis of the regulation and function of NF-κB in latently HIV-1-infected cells has not been done. Here we show that the expression of IκB-α, an endogenous inhibitor of NF-κB, is enhanced by latent HIV-1 infection via induction of the host-derived factor COMMD1/Murr1 in myeloid cells but not in lymphoid cells by using four sets of latently HIV-1-infected cells and the respective parental cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the phosphoinositol 3-kinase (PI3K)-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Our findings indicate that COMMD1 induction is the NF-κB inhibition mechanism in latently HIV-1-infected cells that contributes to innate immune deficiency and reinforces HIV-1 latency. Thus, COMMD1 might be a double-edged sword that is beneficial in primary infection but not beneficial in latent infection when HIV-1 eradication is considered.
HIV-1 latency is a major barrier to viral eradication in the era of combination antiretroviral therapy. In this study, we found that COMMD1/Murr1, previously identified as an HIV-1 restriction factor, inhibits the proteasomal degradation of IκB-α by increasing the interaction with IκB-α in latently HIV-1-infected myeloid cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during the innate immune response and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the PI3K-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Thus, the host-derived factor COMMD1 is beneficial in suppressing primary infection but enhances latent infection, indicating that it may be a double-edged sword in HIV-1 eradication.
转录因子NF-κB对于原发性HIV-1感染中的HIV-1转录起始以及潜伏感染的HIV-1细胞的重新激活很重要。然而，尚未对潜伏感染HIV-1的细胞中NF-κB的调控和功能进行比较分析。在此，我们使用四组潜伏感染HIV-1的细胞及其相应的亲本细胞表明，NF-κB的内源性抑制剂IκB-α的表达通过宿主衍生因子COMMD1/Murr1的诱导在髓细胞中被潜伏感染的HIV-1增强，但在淋巴细胞中未增强。COMMD1使IκB-α蛋白稳定，这在Toll样受体配体和肿瘤坏死因子α处理期间减弱了NF-κB信号传导，并增强了潜伏感染HIV-1的细胞中的HIV-1潜伏性。磷酸肌醇3-激酶（PI3K）-JAK途径的激活参与潜伏感染HIV-1的细胞中COMMD1的诱导。我们的研究结果表明，COMMD1的诱导是潜伏感染HIV-1的细胞中NF-κB的抑制机制，这导致先天免疫缺陷并加强了HIV-1潜伏性。因此，当考虑根除HIV-1时，COMMD1可能是一把双刃剑，在原发性感染中有益，但在潜伏感染中无益。
在联合抗逆转录病毒疗法时代，HIV-1潜伏是病毒根除的主要障碍。在本研究中，我们发现先前被鉴定为HIV-1限制因子的COMMD1/Murr1通过增加与潜伏感染HIV-1的髓细胞中IκB-α的相互作用来抑制IκB-α的蛋白酶体降解。COMMD1使IκB-α蛋白稳定，这在先天免疫反应期间减弱了NF-κB信号传导，并增强了潜伏感染HIV-1的细胞中的HIV-1潜伏性。PI3K-JAK途径的激活参与潜伏感染HIV-1的细胞中COMMD1的诱导。因此，宿主衍生因子COMMD1在抑制原发性感染方面有益，但增强潜伏感染，表明它在根除HIV-1中可能是一把双刃剑。
