Nekongo Emmanuel E, Ponomarenko Anna I, Dewal Mahender B, Butty Vincent L, Browne Edward P, Shoulders Matthew D
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
BioMicro Center, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
ACS Infect Dis. 2020 Jul 10;6(7):1659-1666. doi: 10.1021/acsinfecdis.0c00166. Epub 2020 Jun 10.
Host protein folding stress responses can play important roles in RNA virus replication and evolution. Prior work suggested a complicated interplay between the cytosolic proteostasis stress response, controlled by the transcriptional master regulator heat shock factor 1 (HSF1), and human immunodeficiency virus-1 (HIV-1). We sought to uncouple HSF1 transcription factor activity from cytotoxic proteostasis stress and thereby better elucidate the proposed role(s) of HSF1 in the HIV-1 lifecycle. To achieve this objective, we used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results clarify the interplay between the host's heat shock response and HIV-1 infection and motivate continued investigation of chaperones as potential antiviral therapeutic targets.
宿主蛋白折叠应激反应在RNA病毒复制和进化中可发挥重要作用。先前的研究表明，由转录主调节因子热休克因子1（HSF1）控制的胞质蛋白质稳态应激反应与人类免疫缺陷病毒1型（HIV-1）之间存在复杂的相互作用。我们试图将HSF1转录因子活性与细胞毒性蛋白质稳态应激解耦，从而更好地阐明HSF1在HIV-1生命周期中所提出的作用。为实现这一目标，我们使用化学遗传学方法，对HSF1活性进行与应激无关的控制，以确定HSF1是否以及如何影响HIV-1复制。与应激无关的HSF1诱导降低了HIV-1病毒粒子的总量和感染性。此外，在连续传代过程中，HIV-1无法逃避HSF1介导的限制。这些结果阐明了宿主热休克反应与HIV-1感染之间的相互作用，并促使人们继续研究伴侣蛋白作为潜在的抗病毒治疗靶点。
