HIV-1复制在宿主细胞中受到严格调控,和各种限制因子在抑制病毒复制中具有重要作用。SAMHD1,一个众所周知的限制因素,通过水解细胞内dNTPs抑制HIV-1复制,从而限制了静止细胞中病毒cDNA的合成。在这项研究中,我们揭示了在病毒后cDNA合成阶段SAMHD1抑制的另一种独特机制。使用免疫沉淀和质谱分析,我们证明了SAMHD1和MX2/MxB之间的相互作用,干扰素诱导的抗病毒因子,抑制HIV-1cDNA核输入。内源性MX2表达的破坏显著削弱了SAMHD1抑制HIV-1的能力。已经鉴定了SAMHD1内与MX2结合的关键区域。值得注意的是,我们发现SAMHD1可以作为一个传感器,识别并结合传入的HIV-1核心,随后将其递送至由MX2形成的分子陷阱,从而阻断HIV-1核心结构的核进入。不能识别HIV-1核心的SAMHD1突变体显示出抗病毒活性的显著降低。HIV-1衣壳中的某些突变赋予对MX2抑制的抗性,同时维持对SAMHD1-MX2轴的抑制的易感性。总的来说,我们的研究确定了一个有趣的抗病毒模式,其中两个不同的限制因素,SAMHD1和MX2合作建立了一种偏离其行动的替代机制。这些发现为针对外源性病毒感染的复杂免疫防御网络提供了有价值的见解,并对靶向抗HIV疗法的开发具有意义。
目的:与大多数直接与病毒成分结合以发挥其抗病毒作用的限制性因素相反,SAMHD1,真核生物中唯一已知的脱氧核苷酸三磷酸(dNTP)水解酶,通过减少可用于病毒cDNA合成的dNTP底物库来间接抑制静止细胞中的病毒复制。我们的研究为SAMHD1的抗病毒功能提供了新的视角。除了在dNTP水解中的作用外,SAMHD1与MX2合作抑制HIV-1核进口。在这个过程中,SAMHD1充当传入HIV-1核心的传感器,检测并结合它们,随后将复合物递送至由MX2形成的分子陷阱,从而固定病毒。这项研究不仅揭示了新的抗病毒途径SAMHD1,但也确定了一个独特的合作和两个不同的限制因素之间的相互作用。建立新的防御HIV-1感染的防线,这挑战了传统的制约因素独立行动的观点。总的来说,我们的发现进一步表明了宿主免疫防御网络的复杂性,并为促进宿主抗病毒免疫防御提供了潜在的靶点。
HIV-1 replication is tightly regulated in host cells, and various restriction factors have important roles in inhibiting viral replication. SAMHD1, a well-known restriction factor, suppresses HIV-1 replication by hydrolyzing intracellular dNTPs, thereby limiting the synthesis of viral cDNA in quiescent cells. In this study, we revealed an additional and distinct mechanism of SAMHD1 inhibition during the postviral cDNA synthesis stage. Using immunoprecipitation and mass spectrometry analysis, we demonstrated the interaction between SAMHD1 and MX2/MxB, an interferon-induced antiviral factor that inhibits HIV-1 cDNA nuclear import. The disruption of endogenous MX2 expression significantly weakened the ability of SAMHD1 to inhibit HIV-1. The crucial region within SAMHD1 that binds to MX2 has been identified. Notably, we found that SAMHD1 can act as a sensor that recognizes and binds to the incoming HIV-1 core, subsequently delivering it to the molecular trap formed by MX2, thereby blocking the nuclear entry of the HIV-1 core structure. SAMHD1 mutants unable to recognize the HIV-1 core showed a substantial decrease in antiviral activity. Certain mutations in HIV-1 capsids confer resistance to MX2 inhibition while maintaining susceptibility to suppression by the SAMHD1-MX2 axis. Overall, our study identifies an intriguing antiviral pattern wherein two distinct restriction factors, SAMHD1 and MX2, collaborate to establish an alternative mechanism deviating from their actions. These findings provide valuable insight into the complex immune defense networks against exogenous viral infections and have implications for the development of targeted anti-HIV therapeutics.
OBJECTIVE: In contrast to most restriction factors that directly bind to viral components to exert their antiviral effects, SAMHD1, the only known deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, indirectly inhibits viral replication in quiescent cells by reducing the pool of dNTP substrates available for viral cDNA synthesis. Our study provides a novel perspective on the antiviral functions of SAMHD1. In addition to its role in dNTP hydrolysis, SAMHD1 cooperates with MX2 to inhibit HIV-1 nuclear import. In this process, SAMHD1 acts as a sensor for incoming HIV-1 cores, detecting and binding to them, before subsequently delivering the complex to the molecular trap formed by MX2, thereby immobilizing the virus. This study not only reveals a new antiviral pathway for SAMHD1 but also identifies a unique collaboration and interaction between two distinct restriction factors, establishing a novel line of defense against HIV-1 infection, which challenges the traditional view of restriction factors acting independently. Overall, our findings further indicate the intricate complexity of the host immune defense network and provide potential targets for promoting host antiviral immune defense.