HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4 + T Cells

Vermeíre, Jolien; Roesch, Ferdinand; Sauter, Daniel; Rua, Réjane; Hotter, Dominik; Nuffel, Anouk Van; Vanderstraeten, Hanne; Naessens, Evelien; Iannucci, Veronica; Landi, Alessia; Witkowski, Wojciech; Baeyens, Ann; Kirchhoff, Frank; Verhasselt, Bruno

doi:10.1016/j.celrep.2016.09.023

Cited by 71 publications

(104 citation statements)

References 58 publications

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“…It is important to mention that cGAS can also be implicated in sensing RNA viruses [12]. In an intriguing study, Vermeire et al reported that activated CD4 + T cells sense HIV-1 infection through cGAS, originally described as a DNA sensor, and promote a type I IFN response, although it remains unknown how [49]. Mankan et al showed that cGAS can bind RNA:DNA hybrid to form cGAMP, with subsequent activation of STING [50].…”

Section: Dissecting Sting Signalingmentioning

confidence: 99%

The Emerging Roles of STING in Bacterial Infections

Marinho

Benmerzoug

Oliveira

et al. 2017

Trends in Microbiology

103

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The STING (Stimulator of Interferon Genes) protein connects micro-organism cytosolic sensing with effector functions of the host cell by sensing directly cyclic dinucleotides (CDNs), originating from pathogens or from the host upon DNA recognition. Although STING activation favors effective immune responses against viral infections, its role during bacterial diseases is controversial, ranging from protective to detrimental effects for the host. In this review, we summarize the important features of the STING activation pathway and recent highlights about the role of STING in bacterial infections caused by organisms from the Chlamydia, Listeria, Francisella, Brucella, Shigella, Salmonella, Streptococcus and Neisseria genera, with a special focus on Mycobacterium infections.

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Section: Dissecting Sting Signalingmentioning

confidence: 99%

The Emerging Roles of STING in Bacterial Infections

Marinho

Benmerzoug

Oliveira

et al. 2017

Trends in Microbiology

103

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“…However this response is dependent on endocytosis, and thus is not a byproduct of productive infection. The specific relevance of cGAS-STING signaling in sensing of HIV-1 infection in infected pDCs is still unclear, although human pDCs harbor a functional cGAS-STING pathway [86].…”

Section: Innate Immune Response To Hiv-1 Infection In Dcs and Macrophmentioning

confidence: 99%

Sensor Sensibility—HIV-1 and the Innate Immune Response

Yin

Langer

Zhang

et al. 2020

Cells

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Innate immunity represents the human immune system’s first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) is a unique human RNA virus that causes acquired immunodeficiency syndrome (AIDS) in infected individuals. During the replication cycle, HIV-1 undergoes reverse transcription of its RNA genome and integrates the resulting DNA into the human genome. Subsequently, transcription of the integrated provirus results in production of new virions and spreading infection of the virus. Throughout the viral replication cycle, numerous nucleic acid derived PAMPs can be recognized by a diverse set of innate immune sensors in infected cells. However, HIV-1 has evolved efficient strategies to evade or counteract this immune surveillance and the downstream responses. Understanding the molecular underpinnings of the concerted actions of the innate immune system, as well as the corresponding viral evasion mechanisms during infection, is critical to understanding HIV-1 transmission and pathogenesis, and may provide important guidance for the design of appropriate adjuvant and vaccine strategies. Here, we summarize current knowledge of the molecular basis for sensing HIV-1 in human cells, including CD4+ T cells, dendritic cells, and macrophages. Furthermore, we discuss the underlying mechanisms by which innate sensing is regulated, and describe the strategies developed by HIV-1 to evade sensing and immune responses.

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“…It is reported that Vpr may have a positive effect on IFN-I induction during HIV-1 infection of monocytes-derived DC (MDDCs) or monocytes-derived macrophages (MDMs) (Zahoor et al, 2015;Zahoor et al, 2014). In contrast, others have reported a suppressive role of Vpr on IFN-I production in MDDCs and MDMs (Harman et al, 2011;Mashiba et al, 2014), or in cell lines, such as HEK293, HeLa and HeLa-derived STING-expressing reporter cells (Vermeire et al, 2016).…”

Section: Ifn-i Induces a Number Of Anti-viral Factors To Inhibit Hiv-mentioning

confidence: 99%

HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells

Wang

Tsao

et al. 2019

Preprint

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Plasmacytoid dendritic cells (pDCs) are the major source of type I interferons (IFN-I) in rapid response to viral infections, with constitutive expression of interferon regulatory factor 7 (IRF7). HIV-1 expresses several accessory proteins to counteract specific IFN-induced host restriction factors. As one abundant virion-associated protein, HIV-1 Vpr remains enigmatic in enhancing HIV-1 infection via unclear mechanisms. Here we report that Vpr impaired IFN-I induction in pDCs to enhance HIV-1 replication in CD4+ T cells. Blockade of IFN-I signaling abrogated the effect of Vpr on HIV-1 replication. Virion-associated Vpr suppressed IFN-I induction in pDC by TLR7 agonists. Modulation of IFN-I induction by Vpr was genetically dependent on its activity of TET2 degradation. We further demonstrate that Vpr-mediated TET2 degradation reduced expression of IRF7 in pDCs. Finally, degradation of TET2 in pDCs by Vpr reduced the demethylation level of the IRF7 promoter via CXXC5-dependent recruitment. We conclude that HIV-1 Vpr functions to promote HIV-1 replication by suppressing TET2-dependent IRF7 expression and IFN-I induction in pDCs. The Vpr-TET2-IRF7 axis provides a novel therapeutic target to control HIV-1 infection.

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HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4 + T Cells

Cited by 71 publications

References 58 publications

The Emerging Roles of STING in Bacterial Infections

The Emerging Roles of STING in Bacterial Infections

Sensor Sensibility—HIV-1 and the Innate Immune Response

HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells

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