National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India.
J Mol Biol. 2011 Jul 29;410(5):944-58. doi: 10.1016/j.jmb.2011.04.005.
Cellular heat shock proteins (Hsps) are induced upon heat shock, UV irradiation and microbial or viral infection. They are also known to be involved in apoptosis and immune response in addition to their chaperone function. Although some literature exists regarding the role of Hsps in human immunodeficiency virus (HIV)-1 infection, a clear understanding of their role remains elusive. Previously, we have shown that Hsp40, a co-chaperone of Hsp70, interacts with HIV-1 negative regulatory factor (Nef) and is required for Nef-mediated increase in viral gene expression and replication. We now show that Hsp70 is also present in the Nef-Hsp40 complex reported earlier. Furthermore, Hsp70 inhibits viral gene expression and replication; however, Hsp40 can rescue this down regulation of viral gene expression induced by Hsp70. We also show that HIV-1 viral protein R is required for this inhibitory effect of Hsp70 on viral replication. Our data further show that Hsp40 is consistently up regulated in HIV-1 infection, whereas Hsp70 is down regulated after initial up regulation favoring viral replication. Finally, Hsp70 expression inhibits the phosphorylation of cyclin-dependent kinase 9 required for high-affinity binding of HIV-1 transactivator of transcription-positive transcription elongation factor b complex to transactivation response RNA, whereas Hsp40 seems to induce it. Thus, Hsp40 and Hsp70, both closely associated in their chaperone function, seem to act contrary to each other in regulating viral gene expression. It seems that Hsp70 favors the host by inhibiting viral replication, whereas Hsp40 works in favor of the virus by inducing its replication. Thus, differential expression of Hsp40 and Hsp70 reciprocally regulates viral gene expression and replication in HIV-1 infection.
细胞热休克蛋白（Hsps）在热休克、UV 照射以及微生物或病毒感染时被诱导产生。它们除了具有伴侣功能外，还参与细胞凋亡和免疫反应。尽管有一些关于 Hsps 在人类免疫缺陷病毒（HIV-1）感染中的作用的文献，但对其作用仍缺乏清晰的认识。之前，我们已经表明，Hsp40 是 Hsp70 的共伴侣，与 HIV-1 负调节因子（Nef）相互作用，并且是 Nef 介导的病毒基因表达和复制增加所必需的。我们现在表明，Hsp70 也存在于之前报道的 Nef-Hsp40 复合物中。此外，Hsp70 抑制病毒基因表达和复制；然而，Hsp40 可以挽救 Hsp70 诱导的病毒基因表达的下调。我们还表明，HIV-1 病毒蛋白 R 是 Hsp70 对病毒复制的这种抑制作用所必需的。我们的数据进一步表明，Hsp40 在 HIV-1 感染中持续上调，而 Hsp70 在初始上调后下调，有利于病毒复制。最后，Hsp70 表达抑制了 HIV-1 转录激活因子转录延伸因子 b 复合物高亲和力结合 HIV-1 转录激活反应 RNA 所必需的周期蛋白依赖性激酶 9 的磷酸化，而 Hsp40 似乎诱导了它。因此，在调节病毒基因表达方面，Hsp40 和 Hsp70 这两种在伴侣功能上密切相关的蛋白似乎相互矛盾。似乎 Hsp70 通过抑制病毒复制来有利于宿主，而 Hsp40 通过诱导其复制来有利于病毒。因此，Hsp40 和 Hsp70 的差异表达在 HIV-1 感染中相互调节病毒基因表达和复制。
