SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection.
SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection.
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DOI：
10.1371/journal.ppat.1002425
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Flory E
中科院分区：
文献类型：
--
作者：
Berger A;Sommer AF;Zwarg J;Hamdorf M;Welzel K;Esly N;Panitz S;Reuter A;Ramos I;Jatiani A;Mulder LC;Fernandez-Sesma A;Rutsch F;Simon V;König R;Flory E
骨髓血细胞对人类免疫缺陷病毒1型（HIV-1）的感染有很大的抵抗力。最近，据报道，来自HIV-2/SIVsm的Vpx通过抵消宿主限制因子SAMHD 1而促进这些细胞的感染。在这里，我们独立地证实了Vpx与SAMHD 1相互作用，并靶向其进行泛素介导的降解。我们发现，Vpx介导的SAMHD 1降解使原代单核细胞对HIV-1感染高度敏感; Vpx与T17 A突变，缺陷的SAMHD 1结合和降解，没有显示出这种活性。SAMHD 1基因的几个单核苷酸多态性与Aicardi-Goutières综合征（AGS）相关，AGS是一种非常罕见的严重自身免疫性疾病。来自SAMHD 1（R164 X）无义突变纯合子的AGS患者的原代外周血单核细胞（PBMC）缺乏内源性SAMHD 1表达，并且在不存在外源性激活的情况下支持HIV-1复制。我们的研究结果表明，在AGS患者的PBMC中，CD 14+细胞是对HIV-1感染易感的亚群，而来自健康供体的细胞不支持感染。受感染的SAMHD 1-/-细胞的单核细胞谱系，连同感染前测量的细胞因子、趋化因子和I型干扰素的大多数不可检测的水平，表明异常的细胞活化不是观察到的表型的原因。综上所述，我们认为SAMHD 1可以保护原代CD 14+单核细胞免受HIV-1感染，这证实了SAMHD 1是一种有效的慢病毒限制因子。慢病毒辅助蛋白在拮抗宿主蛋白中发挥重要作用，目的是在细胞水平上抑制HIV-1复制。SIV/HIV-2蛋白Vpx抵消了SAMHD 1，一种以前未知的骨髓血细胞内的抗病毒因子，使这些细胞允许灵长类免疫缺陷病毒。我们在这项研究中证实，Vpx与SAMHD 1相互作用，导致泛素介导的SAMHD 1降解，并使CD 14阳性单核细胞对HIV-1感染易感。我们提供了新的见解SAMHD 1的能力，以保护单核细胞从HIV-1感染，使用原代细胞从患者Aicardi-Goutières综合征（AGS）缺乏内源性SAMHD 1的表达。我们发现，AGS患者的外周血单核细胞对HIV-1具有高度的耐受性。因此，我们的研究表明，SAMHD 1是至关重要的限制HIV-1感染的单核细胞添加SAMHD 1作为一种新的先天性防御因子。
Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor. Lentiviral accessory proteins play important roles in antagonizing host proteins aimed at suppressing HIV-1 replication at a cellular level. The SIV/HIV-2 protein Vpx counteracts SAMHD1, a previously unknown antiviral factor within myeloid blood cells, rendering these cells permissive to primate immunodeficiency viruses. We confirm in this study that Vpx interacts with SAMHD1 leading to ubiquitin-mediated degradation of SAMHD1, and renders CD14 positive monocytes susceptible to HIV-1 infection. We provide new insights into the ability of SAMHD1 to protect monocytic cells from HIV-1 infection by using primary cells from patients with Aicardi-Goutières syndrome (AGS) lacking endogenous SAMHD1 expression. We show that peripheral monocytic cells of AGS patients are highly permissive to HIV-1. Thus, our study demonstrates that SAMHD1 is critical for restriction of HIV-1 infection in monocytes adding SAMHD1 as a novel innate defense factor.
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