HIV-1 infection of noncycling cells, such as dendritic cells (DCs), is impaired due to limited availability of deoxynucleoside triphosphates (dNTPs), which are needed for HIV-1 reverse transcription. The levels of dNTPs are tightly regulated during the cell cycle and depend on the balance between dNTP biosynthesis and degradation. SAMHD1 potently blocks HIV-1 replication in DCs, although the underlying mechanism is still unclear. SAMHD1 has been reported to be able to degrade dNTPs and viral nucleic acids, which may both hamper HIV-1 reverse transcription. The relative contribution of these activities may differ in cycling and noncycling cells. Here, we show that inhibition of HIV-1 replication in monocyte-derived DCs (MDDCs) is associated with an increased expression of p21cip1/waf, a cell cycle regulator that is involved in the differentiation and maturation of DCs. Induction of p21 in MDDCs decreases the pool of dNTPs and increases the antiviral active isoform of SAMHD1. Although both processes are complementary in inhibiting HIV-1 replication, the antiviral activity of SAMHD1 in our primary cell model appears to be, at least partially, independent of its dNTPase activity. The reduction in the pool of dNTPs in MDDCs appears rather mostly due to a p21-mediated suppression of several enzymes involved in dNTP synthesis (i.e., RNR2, TYMS, and TK-1). These results are important to better understand the interplay between HIV-1 and DCs and may inform the design of new therapeutic approaches to decrease viral dissemination and improve immune responses against HIV-1.

IMPORTANCE DCs play a key role in the induction of immune responses against HIV. However, HIV has evolved ways to exploit these cells, facilitating immune evasion and virus dissemination. We have found that the expression of p21, a cyclin-dependent kinase inhibitor involved in cell cycle regulation and monocyte differentiation and maturation, potentially can contribute to the inhibition of HIV-1 replication in monocyte-derived DCs through multiple mechanisms. p21 decreased the size of the intracellular dNTP pool. In parallel, p21 prevented SAMHD1 phosphorylation and promoted SAMHD1 dNTPase-independent antiviral activity. Thus, induction of p21 resulted in conditions that allowed the effective inhibition of HIV-1 replication through complementary mechanisms. Overall, p21 appears to be a key regulator of HIV infection in myeloid cells.

由于脱氧核苷三磷酸（dNTPs）的可用性有限，非循环性细胞（如树突状细胞（DCs））的HIV-1感染受到损害，这是HIV-1逆转录所需的。dNTP的水平在细胞周期中受到严格调节，并取决于dNTP生物合成与降解之间的平衡。SAMHD1可以有效阻止DC中HIV-1的复制，尽管其潜在机制尚不清楚。据报道，SAMHD1能够降解dNTPs和病毒核酸，这都可能阻碍HIV-1逆转录。这些活动的相对贡献可能在循环和非循环细胞中有所不同。在这里，我们表明抑制HIV-1在单核细胞衍生的DC（MDDC）中的复制与p21cip1 / waf的表达增加有关，细胞周期调节剂，参与DC的分化和成熟。MDDC中p21的诱导减少了dNTP的库并增加了SAMHD1的抗病毒活性同工型。尽管这两个过程在抑制HIV-1复制方面是互补的，但在我们的原代细胞模型中，SAMHD1的抗病毒活性似乎至少部分独立于其dNTPase活性。MDDC中dNTP池的减少似乎主要归因于p21介导的dNTP合成中涉及的几种酶（即RNR2，TYMS和TK-1）的抑制。这些结果对于更好地了解HIV-1与DC之间的相互作用非常重要，并且可能有助于设计新的治疗方法以减少病毒的传播并改善针对HIV-1的免疫反应。MDDC中p21的诱导减少了dNTP的库并增加了SAMHD1的抗病毒活性同工型。尽管这两个过程在抑制HIV-1复制方面是互补的，但在我们的原代细胞模型中，SAMHD1的抗病毒活性似乎至少部分独立于其dNTPase活性。MDDC中dNTP池的减少似乎主要归因于p21介导的dNTP合成中涉及的几种酶（即RNR2，TYMS和TK-1）的抑制。这些结果对于更好地了解HIV-1与DC之间的相互作用非常重要，并且可能有助于设计新的治疗方法以减少病毒的传播并改善针对HIV-1的免疫反应。MDDC中p21的诱导减少了dNTP的库并增加了SAMHD1的抗病毒活性同工型。尽管这两个过程在抑制HIV-1复制方面是互补的，但在我们的原代细胞模型中，SAMHD1的抗病毒活性似乎至少部分独立于其dNTPase活性。MDDC中dNTP池的减少似乎主要归因于p21介导的dNTP合成中涉及的几种酶（即RNR2，TYMS和TK-1）的抑制。这些结果对于更好地了解HIV-1与DC之间的相互作用非常重要，并且可能有助于设计新的治疗方法以减少病毒的传播并改善针对HIV-1的免疫反应。SAMHD1在我们的原代细胞模型中的抗病毒活性似乎至少部分独立于其dNTPase活性。MDDC中dNTP池的减少似乎主要归因于p21介导的dNTP合成中涉及的几种酶（即RNR2，TYMS和TK-1）的抑制。这些结果对于更好地了解HIV-1与DC之间的相互作用非常重要，并且可能有助于设计新的治疗方法以减少病毒的传播并改善针对HIV-1的免疫反应。SAMHD1在我们的原代细胞模型中的抗病毒活性似乎至少部分独立于其dNTPase活性。MDDC中dNTP池的减少似乎主要归因于p21介导的dNTP合成中涉及的几种酶（即RNR2，TYMS和TK-1）的抑制。这些结果对于更好地了解HIV-1与DC之间的相互作用非常重要，并且可能有助于设计新的治疗方法以减少病毒的传播并改善针对HIV-1的免疫反应。

重要性DC在诱导针对HIV的免疫应答中起关键作用。但是，艾滋病毒已发展出利用这些细胞的方法，有助于逃避免疫和传播病毒。我们已经发现，p21的表达（一种参与细胞周期调控以及单核细胞分化和成熟的细胞周期蛋白依赖性激酶抑制剂）可能通过多种机制来抑制HIV-1在单核细胞衍生DC中的复制。p21减少了细胞内dNTP库的大小。同时，p21阻止了SAMHD1磷酸化并促进了SAMHD1 dNTPase依赖性抗病毒活性。因此，p21的诱导导致条件允许通过互补机制有效抑制HIV-1复制。总体而言，p21似乎是髓样细胞中HIV感染的关键调节剂。