Tombusvirus-yeast interactions identify conserved cell-intrinsic viral restriction factors

Understanding HIV transmission is critical to guide the development of prophylactic interventions to prevent infection. We used a nonhuman primate (NHP) model with a synthetic swarm of sequence-tagged variants of SIVmac239 (“SIVmac239X”) and scheduled necropsy during primary infection (days 3 to 14 after challenge) to study viral dynamics and host responses to the establishment and dissemination of infection following vaginal challenge. We demonstrate that local replication was initiated at multiple sites within the female genital tract (FGT), with each site having multiple viral variants. Local replication and spread in the FGT preceded lymphatic dissemination. Innate viral restriction factors were observed but appeared to follow viral replication and were ineffective at blocking initial viral establishment and dissemination. However, major delays were observed in time to dissemination in animals and among different viral variants within the same animal. It will be important to assess how phenotypic differences affect early viral dynamics.

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Methadone Inhibits Viral Restriction Factors and Facilitates HIV Infection in Macrophages

Frontiers in Immunology ◽

10.3389/fimmu.2020.01253 ◽

2020 ◽

Vol 11 ◽

Author(s):

Mei-Rong Wang ◽

Di-Di Wu ◽

Fan Luo ◽

Chao-Jie Zhong ◽

Xin Wang ◽

...

Keyword(s):

Hiv Infection ◽

Restriction Factors ◽

Viral Restriction

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West Nile Virus Restriction in Mosquito and Human Cells: A Virus under Confinement

Vaccines ◽

10.3390/vaccines8020256 ◽

2020 ◽

Vol 8 (2) ◽

pp. 256

Author(s):

Marie-France Martin ◽

Sébastien Nisole

Keyword(s):

West Nile Virus ◽

Current Knowledge ◽

Mammalian Species ◽

Human Cells ◽

Health Concern ◽

Broad Host Range ◽

Restriction Factors ◽

West Nile ◽

Viral Propagation ◽

Viral Restriction

West Nile virus (WNV) is an emerging neurotropic flavivirus that naturally circulates between mosquitoes and birds. However, WNV has a broad host range and can be transmitted from mosquitoes to several mammalian species, including humans, through infected saliva during a blood meal. Although WNV infections are mostly asymptomatic, 20% to 30% of cases are symptomatic and can occasionally lead to severe symptoms, including fatal meningitis or encephalitis. Over the past decades, WNV-carrying mosquitoes have become increasingly widespread across new regions, including North America and Europe, which constitutes a public health concern. Nevertheless, mosquito and human innate immune defenses can detect WNV infection and induce the expression of antiviral effectors, so-called viral restriction factors, to control viral propagation. Conversely, WNV has developed countermeasures to escape these host defenses, thus establishing a constant arms race between the virus and its hosts. Our review intends to cover most of the current knowledge on viral restriction factors as well as WNV evasion strategies in mosquito and human cells in order to bring an updated overview on WNV–host interactions.

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Methamphetamine Facilitates HIV Infection of Human Monocytes Through Inhibiting Cellular Viral Restriction Factors

10.21203/rs.3.rs-487867/v1 ◽

2021 ◽

Author(s):

Yu Liu ◽

Fengzhen Meng ◽

xu wang ◽

Jinbiao Liu ◽

Peng Wang ◽

...

Keyword(s):

Immune System ◽

Hiv Infection ◽

Persistent Infection ◽

Human Monocytes ◽

Restriction Factors ◽

Primary Target ◽

Protein Levels ◽

Viral Restriction ◽

P24 Protein ◽

Major Target

Abstract Background Methamphetamine (METH), a potent addictive psychostimulant, is highly prevalent in HIV-infected individuals. Clinically, METH use is implicated in alteration of immune system and increase of HIV spread/replication. Therefore, it is of importance to examine whether METH has direct effect on HIV infection of monocytes, the major target and reservoir cells for the virus. Result METH-treated monocytes were more susceptible to HIV infection as evidenced by increased levels of viral p24 protein and expression of viral GAG gene. Mechanistically, METH treatment of monocytes inhibited the expression of the antiviral IFN-stimulated genes (ISGs: OAS2, GBP5, ISG56, Viperin and ISG15) and the HIV restriction microRNAs. In addition, METH treatment of monocytes significantly decreased STAT1 expression at both mRNA and protein levels. Conclusions These findings suggest a previously unrecognized mechanism for HIV persistent infection in the primary target and reservoir cells.

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Methamphetamine facilitates HIV infection of primary human monocytes through inhibiting cellular viral restriction factors

Cell & Bioscience ◽

10.1186/s13578-021-00703-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu Liu ◽

Feng-Zhen Meng ◽

Xu Wang ◽

Peng Wang ◽

Jin-Biao Liu ◽

...

Keyword(s):

Hiv Infection ◽

Viral Proteins ◽

Luciferase Reporter ◽

Human Monocytes ◽

Restriction Factors ◽

Luciferase Reporter Gene ◽

Hiv Replication ◽

Viral Restriction ◽

Anti Hiv ◽

Major Target

Abstract Background Methamphetamine (METH), a potent addictive psychostimulant, is highly prevalent in HIV-infected individuals. Clinically, METH use is implicated in alteration of immune system and increase of HIV spread/replication. Therefore, it is of importance to examine whether METH has direct effect on HIV infection of monocytes, the major target and reservoir cells for the virus. Results METH-treated monocytes were more susceptible to HIV infection as evidenced by increased levels of viral proteins (p24 and Pr55Gag) and expression of viral GAG gene. In addition, using HIV Bal with luciferase reporter gene (HIV Bal-eLuc), we showed that METH-treated cells expressed higher luciferase activities than untreated monocytes. Mechanistically, METH inhibited the expression of IFN-λ1, IRF7, STAT1, and the antiviral IFN-stimulated genes (ISGs: OAS2, GBP5, ISG56, Viperin and ISG15). In addition, METH down-regulated the expression of the HIV restriction microRNAs (miR-28, miR-29a, miR-125b, miR-146a, miR-155, miR-223, and miR-382). Conclusions METH compromises the intracellular anti-HIV immunity and facilitates HIV replication in primary human monocytes.

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Spir-1 promotes IRF3 activation and is targetted by vaccinia virus protein K7

10.1101/2020.08.31.276659 ◽

2020 ◽

Author(s):

Alice Abreu Torres ◽

Stephanie L. Macilwee ◽

Amir Rashid ◽

Sarah E. Cox ◽

Jonas D. Albarnaz ◽

...

Keyword(s):

Vaccinia Virus ◽

Cellular Protein ◽

Actin Binding ◽

Virus Protein ◽

Restriction Factors ◽

Binding Domains ◽

Dead Box ◽

Viral Restriction ◽

Mouse Cells ◽

Irf3 Activation

AbstractCharacterisation of viral proteins that mediate immune evasion enables identification of host proteins that function in innate immunity and act as viral restriction factors. This is shown here with vaccinia virus (VACV) protein K7. K7 is a virulence factor that inhibits activation of IRF3 and NF-κB and binds the DEAD-box RNA helicase 3 (DDX3). In this study, Spir-1 is characterised as an additional cellular protein bound by K7 during VACV infection. Spir-1 belongs to a family of actin-binding proteins, however its interaction with K7 does not require its actin-binding domains, suggesting a new function. In human and mouse cells lacking Spir-1, IRF3 activation is impaired, whereas, conversely, Spir-1 overexpression enhanced IRF3 activation. Like DDX3, Spir-1 interacts with K7 directly via a diphenylalanine motif that also is required to promote IRF3 activation. The biological importance of Spir-1 in the response to virus infection is shown by enhanced replication/spreading of VACV in Spir-1 knockout cells. Thus Spir-1 is a new viral restriction factor that functions to enhance IRF3 activation.

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Restriction Factors in HIV-1 Disease Progression

Current HIV Research ◽

10.2174/1570162x13666150608104412 ◽

2015 ◽

Vol 13 (6) ◽

pp. 448-461 ◽

Cited By ~ 27

Author(s):

Natacha Merindol ◽

Lionel Berthoux

Keyword(s):

Disease Progression ◽

Restriction Factors ◽

Hiv 1

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The C-terminal domain of feline and bovine SAMHD1 proteins has a crucial role in lentiviral restriction

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.012767 ◽

2020 ◽

Vol 295 (13) ◽

pp. 4252-4264 ◽

Cited By ~ 2

Author(s):

Chu Wang ◽

Kaikai Zhang ◽

Lina Meng ◽

Xin Zhang ◽

Yanan Song ◽

...

Keyword(s):

Proteasomal Degradation ◽

Acid Sites ◽

Accessory Protein ◽

Restriction Profile ◽

Biological Functions ◽

Terminal Domain ◽

Functional Regions ◽

Viral Restriction ◽

Primate Lentiviruses

SAM and HD domain-containing protein 1 (SAMHD1) is a host factor that restricts reverse transcription of lentiviruses such as HIV in myeloid cells and resting T cells through its dNTP triphosphohydrolase (dNTPase) activity. Lentiviruses counteract this restriction by expressing the accessory protein Vpx or Vpr, which targets SAMHD1 for proteasomal degradation. SAMHD1 is conserved among mammals, and the feline and bovine SAMHD1 proteins (fSAM and bSAM) restrict lentiviruses by reducing cellular dNTP concentrations. However, the functional regions of fSAM and bSAM that are required for their biological functions are not well-characterized. Here, to establish alternative models to investigate SAMHD1 in vivo, we studied the restriction profile of fSAM and bSAM against different primate lentiviruses. We found that both fSAM and bSAM strongly restrict primate lentiviruses and that Vpx induces the proteasomal degradation of both fSAM and bSAM. Further investigation identified one and five amino acid sites in the C-terminal domain (CTD) of fSAM and bSAM, respectively, that are required for Vpx-mediated degradation. We also found that the CTD of bSAM is directly involved in mediating bSAM's antiviral activity by regulating dNTPase activity, whereas the CTD of fSAM is not. Our results suggest that the CTDs of fSAM and bSAM have important roles in their antiviral functions. These findings advance our understanding of the mechanism of fSAM- and bSAM-mediated viral restriction and might inform strategies for improving HIV animal models.

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Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽

10.3390/v13050784 ◽

2021 ◽

Vol 13 (5) ◽

pp. 784

Author(s):

Solène Lerolle ◽

Natalia Freitas ◽

François-Loïc Cosset ◽

Vincent Legros

Keyword(s):

Host Cell ◽

Viral Entry ◽

Current Knowledge ◽

Restriction Factors ◽

Antiviral State ◽

Cellular Factors ◽

Pathogenic Viruses ◽

Genome Transcription ◽

Infected Cells ◽

Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

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