National Research Laboratory of Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea.
Graduate Program in Bio-industrial Engineering, College of Life Science and Biotechnology, The Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Int J Mol Sci. 2022 Oct 15;23(20):12340. doi: 10.3390/ijms232012340.
The positive transcription elongation factor b (P-TEFb) is an essential factor that induces transcription elongation and is also negatively regulated by the cellular factor HEXIM1. Previously, the chimeric protein HEXIM1-Tat (HT) was demonstrated to inhibit human immunodeficiency virus-1 (HIV)-1 transcription. In this study, we attempted to develop an improved antiviral protein that specifically binds viral RNA (vRNA) by fusing HT to HIV-1 nucleocapsid (NC). Thus, we synthesized NC-HEXIM1-Tat (NHT) and HEXIM1-Tat-NC (HTN). NHT and HTN inhibited virus proliferation more effectively than HT, and they did not attenuate the function of HT. Notably, NHT and HTN inhibited the infectivity of the progeny virus, whereas HT had no such effect. NHT and HTN selectively and effectively interacted with vRNA and inhibited the proper packaging of the HIV-1 genome. Taken together, our results illustrated that the novel NC-fused chimeric proteins NHT and HTN display novel mechanisms of anti-HIV effects by inhibiting both HIV-1 transcription and packaging.
正转录延伸因子 b (P-TEFb) 是诱导转录延伸的必需因子，也受到细胞因子 HEXIM1 的负调控。先前，嵌合蛋白 HEXIM1-Tat (HT) 被证明可抑制人类免疫缺陷病毒-1 (HIV-1) 转录。在这项研究中，我们试图通过将 HT 与 HIV-1 核衣壳 (NC) 融合来开发一种特异性结合病毒 RNA (vRNA) 的改良抗病毒蛋白。因此，我们合成了 NC-HEXIM1-Tat (NHT) 和 HEXIM1-Tat-NC (HTN)。NHT 和 HTN 比 HT 更有效地抑制病毒增殖，并且它们不会减弱 HT 的功能。值得注意的是，NHT 和 HTN 抑制了子代病毒的感染性，而 HT 则没有这种作用。NHT 和 HTN 选择性且有效地与 vRNA 相互作用，并抑制 HIV-1 基因组的适当包装。总之，我们的结果表明，新型 NC 融合嵌合蛋白 NHT 和 HTN 通过抑制 HIV-1 的转录和包装，显示出新型的抗 HIV 作用机制。
