Vemula Sai Vikram, Veerasamy Ravichandran, Ragupathy Viswanath, Biswas Santanu, Devadas Krishnakumar, Hewlett Indira
Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Viruses. 2015 Feb 5;7(2):543-58. doi: 10.3390/v7020543.
Retroviruses rely on host factors for cell entry, replication, transcription, and other major steps during their life cycle. Human Immunodeficiency Virus-1 (HIV-1) is well known for utilizing a plethora of strategies to evade the host immune response, including the establishment of latent infection within a subpopulation of susceptible cells. HIV-1 also manipulates cellular factors in latently infected cells and persists for long periods of time, despite the presence of successful highly active antiretroviral therapy (HAART).
In this study we demonstrate that Nuclear Factor-IB (NF-IB) is induced during HIV-1 infection and its expression negatively impacts viral replication. During HIV-1 infection in peripheral blood mononuclear cells (PBMCs), and the T cell line, Jurkat or during induction of virus replication in latently infected cells, ACH2 and J1.1, we observed a time-dependent alteration in NF-IB expression pattern that correlated with HIV-1 viral expression. Using the Chip assay, we observed an association of NF-IB with the long terminal repeat region of HIV-1 (LTR) (-386 to -453 nt), and this association negatively correlated with HIV-1 transcription. Furthermore, knock-down of NF-IB levels in J1.1 cells resulted in an increase of HIV-1 levels. Knock-down of NF-IB levels in J-Lat-Tat-GFP (A1), (a Jurkat cell GFP reporter model for latent HIV-1 infection) resulted in an increase in GFP levels, indicating a potential negative regulatory role of NF-IB in HIV-1 replication.
Overall, our results suggest that NF-IB may play a role in intrinsic antiretroviral defenses against HIV-1. These observations may offer new insights into the correlation of the latently infected host cell types and HIV-1, and help to define new therapeutic approaches for triggering the switch from latency to active replication thereby eliminating HIV-1 latent infection.
逆转录病毒在其生命周期的细胞进入、复制、转录及其他主要步骤中依赖宿主因子。人类免疫缺陷病毒1型（HIV-1）以利用大量策略逃避宿主免疫反应而闻名，包括在易感细胞亚群中建立潜伏感染。尽管有成功的高效抗逆转录病毒疗法（HAART），HIV-1仍会操纵潜伏感染细胞中的细胞因子并长期持续存在。
在本研究中，我们证明核因子-κB（NF-κB）在HIV-1感染期间被诱导，其表达对病毒复制产生负面影响。在外周血单核细胞（PBMC）和T细胞系Jurkat中进行HIV-1感染期间，以及在潜伏感染细胞ACH2和J1.1中诱导病毒复制期间，我们观察到NF-κB表达模式随时间的变化，这与HIV-1病毒表达相关。使用染色质免疫沉淀分析（Chip分析），我们观察到NF-κB与HIV-1的长末端重复序列区域（LTR）（-386至-453核苷酸）存在关联，且这种关联与HIV-1转录呈负相关。此外，J1.1细胞中NF-κB水平的敲低导致HIV-1水平升高。在J-Lat-Tat-GFP（A1）（一种用于潜伏HIV-1感染的Jurkat细胞GFP报告模型）中敲低NF-κB水平导致GFP水平升高，表明NF-κB在HIV-1复制中可能具有潜在的负调控作用。
总体而言，我们的结果表明NF-κB可能在针对HIV-1的固有抗逆转录病毒防御中发挥作用。这些观察结果可能为潜伏感染的宿主细胞类型与HIV-1之间的相关性提供新的见解，并有助于确定新的治疗方法，以触发从潜伏到活跃复制的转变，从而消除HIV-1潜伏感染。
