Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, China.
AIDS. 2011 Jan 2;25(1):15-25. doi: 10.1097/QAD.0b013e328340fd61.
HIV-1 transactivator protein, Tat, has been identified as an activator of HIV-1 replication. It also dysregulates cytokine production and apoptosis in T-cells. Of the various cell death processes, autophagy is a self-digestion and degradation mechanism that recycles the contents of the cytosol, including macromolecules and cellular organelles, resulting in self-repair and conservation for survival. Recent reports demonstrated that autophagosomes can be activated by interferon-γ (IFN-γ) to participate in immune defence by processing foreign antigens for the recognition and killing of intracellular pathogens. As we previously showed that HIV-1 Tat perturbs IFN-γ signaling through the suppression of STAT1 phosphorylation and consequently inhibits major histocompatibility complex class-II antigen expression, we postulate that Tat plays a role in regulating autophagy.
The role of STAT1 in IFN-γ-induced autophagy in primary human blood macrophages was examined using a small molecule inhibitor or siRNA specific for STAT1. The effect of HIV-1 Tat on autophagy was investigated by pretreating the macrophages with HIV-1 Tat and followed by IFN-γ stimulation. The expressions of autophagy-associated genes and their effects on engulfing mycobacteria were examined.
The activation of STAT1 resulted in IFN-γ-induced LC3B protein expression and autophagosome formation. As postulated, HIV-1 Tat protein suppressed IFN-γ-induced autophagy processes, including LC3B expression. Additionally, HIV-1 Tat restricted the capturing of mycobacteria by autophagosomes.
HIV-1 Tat suppressed the induction of autophagy-associated genes and inhibited the formation of autophagosomes. Perturbation of such cellular processes by HIV-1 would impair the effective containment of invading pathogens, thereby providing a favorable environment for opportunistic microbes in HIV-infected individuals.
HIV-1 转录激活蛋白 Tat 已被鉴定为 HIV-1 复制的激活剂。它还会使 T 细胞中的细胞因子产生和细胞凋亡失调。在各种细胞死亡过程中，自噬是一种自我消化和降解机制，可回收细胞质中的内容物，包括大分子和细胞细胞器，从而实现自我修复和生存的保存。最近的报告表明，自噬体可以被干扰素-γ（IFN-γ）激活，通过处理外来抗原参与免疫防御，以识别和杀死细胞内病原体。由于我们之前表明 HIV-1 Tat 通过抑制 STAT1 磷酸化来干扰 IFN-γ 信号传导，从而抑制主要组织相容性复合物 II 类抗原表达，因此我们假设 Tat 在调节自噬中起作用。
使用小分子抑制剂或针对 STAT1 的 siRNA 检查 STAT1 在原发性人血巨噬细胞中 IFN-γ诱导的自噬中的作用。通过用 HIV-1 Tat 预处理巨噬细胞，然后用 IFN-γ 刺激来研究 HIV-1 Tat 对自噬的影响。检查自噬相关基因的表达及其对吞噬分枝杆菌的影响。
STAT1 的激活导致 IFN-γ 诱导的 LC3B 蛋白表达和自噬体形成。如假设的那样，HIV-1 Tat 蛋白抑制了 IFN-γ 诱导的自噬过程，包括 LC3B 表达。此外，HIV-1 Tat 限制了自噬体对分枝杆菌的捕获。
HIV-1 Tat 抑制了自噬相关基因的诱导，并抑制了自噬体的形成。HIV-1 对这些细胞过程的干扰会损害有效遏制入侵病原体的能力，从而为 HIV 感染者中的机会性微生物提供有利环境。
