Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States of America.
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, United States of America.
PLoS Pathog. 2018 Apr 23;14(4):e1007012. doi: 10.1371/journal.ppat.1007012. eCollection 2018 Apr.
The bromodomain protein Brd4 promotes HIV-1 latency by competitively inhibiting P-TEFb-mediated transcription induced by the virus-encoded Tat protein. Brd4 is recruited to the HIV LTR by interactions with acetyl-histones3 (AcH3) and AcH4. However, the precise modification pattern that it reads and the writer for generating this pattern are unknown. By examining a pool of latently infected proviruses with diverse integration sites, we found that the LTR characteristically has low AcH3 but high AcH4 content. This unusual acetylation profile attracts Brd4 to suppress the interaction of Tat with the host super elongation complex (SEC) that is essential for productive HIV transcription and latency reversal. KAT5 (lysine acetyltransferase 5), but not its paralogs KAT7 and KAT8, is found to promote HIV latency through acetylating H4 on the provirus. Antagonizing KAT5 removes AcH4 and Brd4 from the LTR, enhances the SEC loading, and reverses as well as delays, the establishment of latency. The pro-latency effect of KAT5 is confirmed in a primary CD4+ T cell latency model as well as cells from ART-treated patients. Our data thus indicate the KAT5-AcH4-Brd4 axis as a key regulator of latency and a potential therapeutic target to reactivate latent HIV reservoirs for eradication.
溴结构域蛋白 Brd4 通过竞争性抑制病毒编码的 Tat 蛋白诱导的 P-TEFb 介导的转录，促进 HIV-1 潜伏期。Brd4 通过与乙酰化组蛋白 3（AcH3）和 AcH4 的相互作用被招募到 HIV LTR。然而，它读取的确切修饰模式以及生成该模式的“写入器”尚不清楚。通过检查一组具有不同整合位点的潜伏感染前病毒，我们发现 LTR 特征是低 AcH3 但高 AcH4 含量。这种不寻常的乙酰化模式吸引 Brd4 抑制 Tat 与宿主超延伸复合物（SEC）的相互作用，SEC 对于 HIV 的有效转录和潜伏期逆转至关重要。发现赖氨酸乙酰转移酶 5（KAT5），而不是其旁系同源物 KAT7 和 KAT8，通过乙酰化前病毒上的 H4 来促进 HIV 潜伏期。拮抗 KAT5 可将 AcH4 和 Brd4 从前病毒中去除，增强 SEC 装载，并逆转和延迟潜伏期的建立。KAT5 的促潜伏期作用在原代 CD4+T 细胞潜伏期模型以及来自接受 ART 治疗的患者的细胞中得到证实。因此，我们的数据表明 KAT5-AcH4-Brd4 轴是潜伏期的关键调节剂，是重新激活潜伏 HIV 储库以根除的潜在治疗靶点。
