Previous work has demonstrated that the epitranscriptomic addition of m⁶A to viral transcripts can promote the replication and pathogenicity of a wide range of DNA and RNA viruses, including HIV-1, yet the underlying mechanisms responsible for this effect have remained unclear. It is known that m⁶A function is largely mediated by cellular m⁶A binding proteins or readers, yet how these regulate viral gene expression in general, and HIV-1 gene expression in particular, has been controversial. Here, we confirm that m⁶A addition indeed regulates HIV-1 RNA expression and demonstrate that this effect is largely mediated by the nuclear m⁶A reader YTHDC1 and the cytoplasmic m⁶A reader YTHDF2. Both YTHDC1 and YTHDF2 bind to multiple distinct and overlapping sites on the HIV-1 RNA genome, with YTHDC1 recruitment serving to regulate the alternative splicing of HIV-1 RNAs. Unexpectedly, while YTHDF2 binding to m⁶A residues present on cellular mRNAs resulted in their destabilization as previously reported, YTHDF2 binding to m⁶A sites on HIV-1 transcripts resulted in a marked increase in the stability of these viral RNAs. Thus, YTHDF2 binding can exert diametrically opposite effects on RNA stability, depending on RNA sequence context.

中文翻译：

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m6A 的表观转录组学添加调节 HIV-1 RNA 稳定性和选择性剪接

先前的研究表明，将 m ⁶ A 添加到病毒转录物中可以促进多种 DNA 和 RNA 病毒（包括 HIV-1）的复制和致病性，但造成这种影响的潜在机制仍不清楚。众所周知，m ⁶ A 功能主要由细胞 m ⁶ A 结合蛋白或阅读器介导，但这些通常如何调节病毒基因表达，尤其是 HIV-1 基因表达，一直存在争议。在这里，我们确认 m ⁶ A 的添加确实调节了 HIV-1 RNA 的表达，并证明这种效应主要由核 m ⁶ A 读取器 YTHDC1 和细胞质 m ^6介导读者 YTHDF2。YTHDC1 和 YTHDF2 都与 HIV-1 RNA 基因组上多个不同且重叠的位点结合，YTHDC1 募集用于调节 HIV-1 RNA 的可变剪接。出乎意料的是，虽然 YTHDF2 与细胞 mRNA 上存在的 m ⁶ A 残基结合导致它们不稳定，如先前报道的那样，YTHDF2 与 HIV-1 转录本上的 m ⁶ A 位点结合导致这些病毒 RNA 的稳定性显着增加。因此，YTHDF2 结合可以对 RNA 稳定性产生截然相反的影响，这取决于 RNA 序列上下文。