Methadone Inhibits Viral Restriction Factors and Facilitates HIV Infection in Macrophages

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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Restriction Factors: From Intrinsic Viral Restriction to Shaping Cellular Immunity Against HIV-1

Frontiers in Immunology ◽

10.3389/fimmu.2018.02876 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 37

Author(s):

Marta Colomer-Lluch ◽

Alba Ruiz ◽

Arnaud Moris ◽

Julia G. Prado

Keyword(s):

Cellular Immunity ◽

Restriction Factors ◽

Viral Restriction ◽

Hiv 1

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Interplay between Intrinsic and Innate Immunity during HIV Infection

Cells ◽

10.3390/cells8080922 ◽

2019 ◽

Vol 8 (8) ◽

pp. 922 ◽

Cited By ~ 9

Author(s):

Louis Bergantz ◽

Frédéric Subra ◽

Eric Deprez ◽

Olivier Delelis ◽

Clémence Richetta

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Hiv Infection ◽

Type I ◽

Restriction Factors ◽

Intrinsic Immunity ◽

First Line ◽

Hiv Replication ◽

Interferon Stimulated Genes ◽

Immunodeficiency Virus

Restriction factors are antiviral components of intrinsic immunity which constitute a first line of defense by blocking different steps of the human immunodeficiency virus (HIV) replication cycle. In immune cells, HIV infection is also sensed by several pattern recognition receptors (PRRs), leading to type I interferon (IFN-I) and inflammatory cytokines production that upregulate antiviral interferon-stimulated genes (ISGs). Several studies suggest a link between these two types of immunity. Indeed, restriction factors, that are generally interferon-inducible, are able to modulate immune responses. This review highlights recent knowledge of the interplay between restriction factors and immunity inducing antiviral defenses. Counteraction of this intrinsic and innate immunity by HIV viral proteins will also be discussed.

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Defining early SIV replication and dissemination dynamics following vaginal transmission

Science Advances ◽

10.1126/sciadv.aav7116 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaav7116 ◽

Cited By ~ 8

Author(s):

Claire Deleage ◽

Taina T. Immonen ◽

Christine M. Fennessey ◽

Arnold Reynaldi ◽

Carolyn Reid ◽

...

Keyword(s):

Primary Infection ◽

Hiv Transmission ◽

Female Genital Tract ◽

Host Responses ◽

Viral Dynamics ◽

Restriction Factors ◽

Phenotypic Differences ◽

Viral Restriction ◽

Vaginal Transmission ◽

Female Genital

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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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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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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