Tripartite motif-containing protein 5α (TRIM5α) is generally known to block the postentry events of HIV-1. Here, we report an uncharacterized role for TRIM5α in the maintenance of viral latency. Knockdown of TRIM5α potentiates the transcription of HIV-1 in multiple latency models, which is reversed by shRNA-resistant TRIM5α. TRIM5α suppresses TNFα-activated HIV-1 LTR-driven as well as NF-κB- and Sp1-driven gene expression, with the RING and B-box 2 domains being the essential determinants. Mechanistically, TRIM5α binds to and enhances the recruitment of histone deacetylase 1 (HDAC1) to NF-κB p50 and Sp1. ChIP‒qPCR analyses further reveal that the association of TRIM5α with HIV-1 LTR induces HDAC1 recruitment and local H3K9 deacetylation. Conserved suppression effects of TRIM5α orthologs from multiple species on both HIV-1 and endo-retroelement HERV-K LTR activities have also been demonstrated. These findings provide new insights into the molecular mechanisms by which proviral latency is initially established and activatable proviruses are resilenced by histone deacetylase recruitment.

众所周知，含有三联基序的蛋白 5α (TRIM5α) 可以阻断 HIV-1 的进入后事件。在这里，我们报告了 TRIM5α 在维持病毒潜伏期中的未表征的作用。TRIM5α 的敲低会增强多个潜伏模型中 HIV-1 的转录，而 shRNA 抗性 TRIM5α 则可逆转这种转录。TRIM5α 抑制 TNFα 激活的 HIV-1 LTR 驱动以及 NF-κB 和 Sp1 驱动的基因表达，其中 RING 和 B-box 2 结构域是重要的决定因素。从机制上讲，TRIM5α 结合并增强组蛋白脱乙酰酶 1 (HDAC1) 向 NF-κB p50 和 Sp1 的募集。ChIP-qPCR 分析进一步揭示 TRIM5α 与 HIV-1 LTR 的关联诱导 HDAC1 募集和局部 H3K9 脱乙酰化。来自多个物种的 TRIM5α 直向同源物对 HIV-1 和内逆转录因子 HERV-K LTR 活性的保守抑制作用也已得到证实。这些发现为原病毒潜伏期最初建立和可激活原病毒通过组蛋白脱乙酰酶招募而恢复沉默的分子机制提供了新的见解。