Epitranscriptomic RNA modifications, including methylation of adenine and cytidine residues, are now recognized as key regulators of both cellular and viral mRNA function. Moreover, acetylation of the N⁴ position of cytidine (ac4C) was recently reported to increase the translation and stability of cellular mRNAs. Here, we show that ac4C and N-acetyltransferase 10 (NAT10), the enzyme that adds ac4C to RNAs, have been subverted by human immunodeficiency virus 1 (HIV-1) to increase viral gene expression. HIV-1 transcripts are modified with ac4C at multiple discrete sites, and silent mutagenesis of these ac4C sites led to decreased HIV-1 gene expression. Similarly, loss of ac4C from viral transcripts due to depletion of NAT10 inhibited HIV-1 replication by reducing viral RNA stability. Interestingly, the NAT10 inhibitor remodelin could inhibit HIV-1 replication at concentrations that have no effect on cell viability, thus identifying ac4C addition as a potential target for antiviral drug development.

表观转录组学 RNA 修饰，包括腺嘌呤和胞苷残基的甲基化，现在被认为是细胞和病毒 mRNA 功能的关键调节因子。此外，N ^{4 的}乙酰化最近有报道称胞苷 (ac4C) 的位置可以增加细胞 mRNA 的翻译和稳定性。在这里，我们展示了 ac4C 和 N-乙酰转移酶 10 (NAT10)（将 ac4C 添加到 RNA 的酶）已被人类免疫缺陷病毒 1 (HIV-1) 颠覆以增加病毒基因表达。HIV-1 转录本在多个离散位点被 ac4C 修饰，这些 ac4C 位点的无声突变导致 HIV-1 基因表达降低。类似地，由于 NAT10 耗尽导致病毒转录本中 ac4C 的丢失通过降低病毒 RNA 稳定性来抑制 HIV-1 复制。有趣的是，NAT10 抑制剂 remodelin 可以在对细胞活力没有影响的浓度下抑制 HIV-1 复制，从而将 ac4C 添加确定为抗病毒药物开发的潜在目标。