Retrovirus integration is an obligatory step for the viral life cycle, but large amounts of unintegrated DNA (uDNA) accumulate during retroviral infection. For simple retroviruses, in the absence of integration, viral genomes are epigenetically silenced in host cells. For complex retroviruses such as HIV, preintegration transcription has been found to occur at low levels from a large population of uDNA even in the presence of host epigenetic silencing mechanisms. HIV preintegration transcription has been suggested to be a normal early process of HIV infection that leads to the syntheses of all three classes of viral transcripts: multiply-spliced, singly-spliced, and unspliced genomic RNA; only viral early proteins such as Nef are selectively translated at low levels in blood CD4 T cells and macrophages, the primary targets of HIV. The initiation and persistence of HIV preintegration transcription have been suggested to rely on viral accessory proteins, particularly virion Vpr and de novo Tat generated from uDNA; both proteins have been shown to antagonize host epigenetic silencing of uDNA. In addition, stimulation of latently infected resting T cells and macrophages with cytokines, PKC activator, or histone deacetylase inhibitors has been found to greatly upregulate preintegration transcription, leading to low-level viral production or even replication from uDNA. Functionally, Nef synthesized from preintegration transcription is biologically active in modulating host immune functions, lowering the threshold of T cell activation, and downregulating surface CD4, CXCR4/CCR5, and HMC receptors. The early Tat activity from preintegration transcription antagonizes repressive minichromatin assembled onto uDNA. The study of HIV preintegration transcription is important to understanding virus-host interaction and antagonism, viral persistence, and the mechanism of integrase drug resistance. The application of unintegrated lentiviral vectors for gene therapy also offers a safety advantage for minimizing retroviral vector-mediated insertional mutagenesis.

中文翻译：

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HIV 整合前转录和宿主拮抗

逆转录病毒整合是病毒生命周期的必经步骤，但逆转录病毒感染过程中会积累大量未整合的DNA (uDNA)。对于简单的逆转录病毒，在没有整合的情况下，病毒基因组在宿主细胞中被表观遗传沉默。对于 HIV 等复杂的逆转录病毒，即使存在宿主表观遗传沉默机制，大量 uDNA 中也会发生低水平的预整合转录。HIV 整合前转录被认为是 HIV 感染的正常早期过程，导致所有三类病毒转录物的合成：多剪接、单剪接和未剪接的基因组 RNA；只有病毒早期蛋白（例如 Nef）会在血液 CD4 T 细胞和巨噬细胞（HIV 的主要目标）中以低水平选择性翻译。HIV 预整合转录的启动和持续存在依赖于病毒辅助蛋白，特别是由 uDNA 产生的病毒粒子 Vpr 和 de novo Tat；这两种蛋白质已被证明可以拮抗宿主 uDNA 的表观遗传沉默。此外，用细胞因子、PKC 激活剂或组蛋白脱乙酰酶抑制剂刺激潜伏感染的静息 T 细胞和巨噬细胞，可以极大地上调预整合转录，导致低水平的病毒产生，甚至从 uDNA 复制。从功能上讲，由预整合转录合成的 Nef 在调节宿主免疫功能、降低 T 细胞激活阈值以及下调表面 CD4、CXCR4/CCR5 和 HMC 受体方面具有生物活性。预整合转录产生的早期 Tat 活性拮抗组装到 uDNA 上的抑制性小染色质。HIV整合前转录的研究对于理解病毒-宿主相互作用和拮抗作用、病毒持久性以及整合酶耐药机制具有重要意义。未整合的慢病毒载体在基因治疗中的应用还为最大限度地减少逆转录病毒载体介导的插入突变提供了安全优势。