Inhibition of Hepatitis B virus replication by SAMHD1

Chen, Zhangming; Zhu, Mengying; Pan, Xiang; Zhu, Yingchun; Yan, Hai; Jiang, Tongcui; Shen, Yujun; Dong, Xiaowan; Nan, Zheng; Lu, Jinsen; Shi, Ying

doi:10.1016/j.bbrc.2014.07.023

Cited by 72 publications

(79 citation statements)

References 27 publications

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“…In contrast to the findings of Chen at al 34,. in our experiments, mutation of the active center of the HD domain (D311A) abrogated the inhibitory effect of SAMHD1 (Fig.…”

Section: Discussioncontrasting

confidence: 68%

Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle

Sommer

Rivière

et al. 2016

Sci Rep

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Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of the restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV replication. We demonstrated that silencing of SAMHD1 in hepatic cells increased HBV replication, while overexpression had the opposite effect. SAMHD1 significantly affected the levels of extracellular viral DNA as well as intracellular reverse transcription products, without affecting HBV RNAs or cccDNA. SAMHD1 mutations that interfere with the dNTPase activity (D137N) or in the catalytic center of the histidine-aspartate (HD) domain (D311A), and a phospho-mimetic mutation (T592E), abrogated the inhibitory activity. In contrast, a mutation diminishing the potential RNase but not dNTPase activity (Q548A) and a mutation disabling phosphorylation (T592A) did not affect antiviral activity. Moreover, HBV restriction by SAMHD1 was rescued by addition of deoxynucleosides. Although HBV infection did not directly affect protein level or phosphorylation of SAMHD1, the virus upregulated intracellular dATPs. Interestingly, SAMHD1 was dephosphorylated, thus in a potentially antiviral-active state, in primary human hepatocytes. Furthermore, SAMHD1 was upregulated by type I and II interferons in hepatic cells. These results suggest that SAMHD1 is a relevant restriction factor for HBV and restricts reverse transcription through its dNTPase activity.

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“…In contrast to the findings of Chen at al 34,. in our experiments, mutation of the active center of the HD domain (D311A) abrogated the inhibitory effect of SAMHD1 (Fig.…”

Section: Discussioncontrasting

confidence: 68%

Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle

Sommer

Rivière

et al. 2016

Sci Rep

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“…Reverse transcription, which occurs within the capsid (Fig. 8, step 11), has been demonstrated to be inhibited by SAMHD1 (HBV and HIV) (35,49) and NT5C3A (IAV and CSFV) (50, 51); these proteins were upregulated in our study upon treatment. Proteins that might interfere with viral assembly (Fig.…”

Section: Validation Of Responses To Ifn-3 Treatment In Hbv-transfectesupporting

confidence: 54%

Comprehensive Proteomics Identification of IFN-λ3-regulated Antiviral Proteins in HBV-transfected Cells

Makjaroen

Somparn

Hodge

et al. 2018

Molecular & Cellular Proteomics

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Interferon lambda (IFN-λ) is a relatively unexplored, yet promising antiviral agent. IFN-λ has recently been tested in clinical trials of chronic hepatitis B virus infection (CHB), with the advantage that side effects may be limited compared with IFN-α, as IFN-λ receptors are found only in epithelial cells. To date, IFN-λ's downstream signaling pathway remains largely unelucidated, particularly via proteomics methods. Here, we report that IFN-λ3 inhibits HBV replication in HepG2.2.15 cells, reducing levels of both HBV transcripts and intracellular HBV DNA. Quantitative proteomic analysis of HBV-transfected cells was performed following 24-hour IFN-λ3 treatment, with parallel IFN-α2a and PBS treatments for comparison using a dimethyl labeling method. The depth of the study allowed us to map the induction of antiviral proteins to multiple points of the viral life cycle, as well as facilitating the identification of antiviral proteins not previously known to be elicited upon HBV infection ( IFITM3, XRN2, and NT5C3A). This study also shows up-regulation of many effectors involved in antigen processing/presentation indicating that this cytokine exerted immunomodulatory effects through several essential molecules for these processes. Interestingly, the 2 subunits of the immunoproteasome cap (PSME1 and PSME2) were up-regulated whereas cap components of the constitutive proteasome were down-regulated upon both IFN treatments, suggesting coordinated modulation toward the antigen processing/presentation mode. Furthermore, in addition to confirming canonical activation of interferon-stimulated gene (ISG) transcription through the JAK-STAT pathway, we reveal that IFN-λ3 restored levels of RIG-I and RIG-G, proteins known to be suppressed by HBV. Enrichment analysis demonstrated that several biological processes including RNA metabolism, translation, and ER-targeting were differentially regulated upon treatment with IFN-λ3 IFN-α2a. Our proteomic data suggests that IFN-λ3 regulates an array of cellular processes to control HBV replication.

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“…Additionally, SAMHD1 has been reported to restrict the double‐stranded DNA viruses, vaccinia, and Herpes simplex virus type 1, in nondividing target cells through its dNTP triphosphohydrolase activity . The SAMHD1 inhibited replication of a third DNA virus, hepatitis B virus , in liver cells, which has been further confirmed by 2 recent studies . Moreover, it was reported that porcine SAMHD1 restricts replication of the highly pathogenic porcine reproductive and respiratory syndrome virus, which is a positive‐stranded RNA virus .…”

Section: Structure Of Samhd1 and Its Antiviral Activitymentioning

confidence: 66%

Roles of SAMHD1 in antiviral defense, autoimmunity and cancer

Zhang

Zhu

et al. 2017

Reviews in Medical Virology

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The enzyme, sterile α motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) diminishes infection of human immunodeficiency virus type 1 (HIV-1) by hydrolyzing intracellular deoxynucleotide triphosphates (dNTPs) in myeloid cells and resting CD4+ T cells. This dNTP degradation reduces the dNTP concentration to a level insufficient for viral cDNA synthesis, thereby inhibiting retroviral replication. This antiviral enzymatic activity can be inhibited by viral protein X (Vpx). The HIV-2/SIV Vpx causes degradation of SAMHD1, thus interfering with the SAMHD1-mediated restriction of retroviral replication. Recently, SAMHD1 has been suggested to restrict HIV-1 infection by directly digesting genomic HIV-1 RNA through a still controversial RNase activity. Here, we summarize the current knowledge about structure, antiviral mechanisms, intracellular localization, interferon-regulated expression of SAMHD1. We also describe SAMHD1-deficient animal models and an antiviral drug on the basis of disrupting proteasomal degradation of SAMHD1. In addition, the possible roles of SAMHD1 in regulating innate immune sensing, Aicardi-Goutières syndrome and cancer are discussed in this review.

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Inhibition of Hepatitis B virus replication by SAMHD1

Cited by 72 publications

References 27 publications

Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle

Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle

Comprehensive Proteomics Identification of IFN-λ3-regulated Antiviral Proteins in HBV-transfected Cells

Roles of SAMHD1 in antiviral defense, autoimmunity and cancer

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