Interferon but not MxB inhibits foamy retroviruses

Bähr, Ariane; Singer, Anna; Hain, Anika; Vasudevan, Ananda Ayyappan Jaguva; Schilling, Mirjam; Reh, Juliane; Rieß, Maximilian; Panitz, Sylvia; Serrano, Vanessa; Schweizer, Matthias; König, Renate; Chanda, Sumit K.; Häussinger, Dieter; Kochs, Georg; Lindemann, Dirk; Münk, Carsten

doi:10.1016/j.virol.2015.10.034

Cited by 24 publications

(13 citation statements)

References 78 publications

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“…In contrast to human immunodeficiency virus (HIV) and human T-cell leukemia virus (HTLV), FVs appear to be nonpathogenic in either naturally or accidentally infected hosts and maintain a lifelong infection in the host [2, 3]. Several host factors, such as Trim5α, APOBEC3G and Nmi have been studied as restrictors during PFV replication [4–8]. Previously, we also reported that Pirh2 inhibits PFV replication by degrading the viral trans-activator Tas via ubiquitination [9].…”

Section: Resultsmentioning

confidence: 99%

Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway

et al. 2017

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BackgroundPrototype foamy virus (PFV) is a member of the Spumaretrovirinae subfamily of retroviruses, which maintains lifelong latent infection while being nonpathogenic to their natural hosts. Autophagy is a cell-programmed mechanism that plays a pivotal role in controlling homeostasis and defense against exotic pathogens. However, whether autophagy is the mechanism for host defense in PFV infection has not been investigated.FindingsOur results revealed that PFV infection induced the accumulation of autophagosomes and triggered complete autophagic flux in BHK-21 cells. PFV infection also altered endoplasmic reticulum (ER) homeostasis. The PERK, IRE1 and ATF6 pathways, all of which are components of the ER stress-related unfolded protein response (UPR), were activated in PFV-infected cells. In addition, accelerating autophagy suppressed PFV replication, and inhibition of autophagy promoted viral replication.ConclusionsOur data indicate that PFV infection can induce complete autophagy through activating the ER stress-related UPR pathway in BHK-21 cells. In turn, autophagy negatively regulates PFV replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0341-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway

et al. 2017

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“…9 c). We performed a similar experiment using a HIV-2 luciferase reporter virus [ 64 ], which is a three-plasmid lentiviral vector system that requires Vif to be co-expressed from a separate plasmid (Fig. 9 b).…”

Section: Resultsmentioning

confidence: 99%

Determinants of FIV and HIV Vif sensitivity of feline APOBEC3 restriction factors

Zhang

Vasudevan

et al. 2016

Retrovirology

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BackgroundFeline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a model system for Human immunodeficiency virus (HIV)-induced AIDS. In felids such as the domestic cat (Felis catus), APOBEC3 (A3) genes encode for single-domain A3Z2s, A3Z3 and double-domain A3Z2Z3 anti-viral cytidine deaminases. The feline A3Z2Z3 is expressed following read-through transcription and alternative splicing, introducing a previously untranslated exon in frame, encoding a domain insertion called linker. Only A3Z3 and A3Z2Z3 inhibit Vif-deficient FIV. Feline A3s also are restriction factors for HIV and Simian immunodeficiency viruses (SIV). Surprisingly, HIV-2/SIV Vifs can counteract feline A3Z2Z3.ResultsTo identify residues in feline A3s that Vifs need for interaction and degradation, chimeric human–feline A3s were tested. Here we describe the molecular direct interaction of feline A3s with Vif proteins from cat FIV and present the first structural A3 model locating these interaction regions. In the Z3 domain we have identified residues involved in binding of FIV Vif, and their mutation blocked Vif-induced A3Z3 degradation. We further identified additional essential residues for FIV Vif interaction in the A3Z2 domain, allowing the generation of FIV Vif resistant A3Z2Z3. Mutated feline A3s also showed resistance to the Vif of a lion-specific FIV, indicating an evolutionary conserved Vif–A3 binding. Comparative modelling of feline A3Z2Z3 suggests that the residues interacting with FIV Vif have, unlike Vif-interacting residues in human A3s, a unique location at the domain interface of Z2 and Z3 and that the linker forms a homeobox-like domain protruding of the Z2Z3 core. HIV-2/SIV Vifs efficiently degrade feline A3Z2Z3 by possible targeting the linker stretch connecting both Z-domains.ConclusionsHere we identified in feline A3s residues important for binding of FIV Vif and a unique protein domain insertion (linker). To understand Vif evolution, a structural model of the feline A3 was developed. Our results show that HIV Vif binds human A3s differently than FIV Vif feline A3s. The linker insertion is suggested to form a homeo-box domain, which is unique to A3s of cats and related species, and not found in human and mouse A3s. Together, these findings indicate a specific and different A3 evolution in cats and human.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0274-9) contains supplementary material, which is available to authorized users.

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“…All vector constructs were verified by sequencing and tested for USP18 protein expression. HIV-1 vector, pSIN.PPT.CMV.Luc.IRES.GFP (75,76), HIV-2 virus containing HIV-2 construct (pHIV-2D4), and pHIV-2 Luc SV40 (previously called pHIV-2 SEW Luc SV40) have been described before (76). The HIV-1 construct psPAX2 was obtained from the NIH, AIDS Reagent Program repository.…”

Section: Plasmidsmentioning

confidence: 99%

USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1

Kuffour

Schott

Vasudevan

et al. 2018

J Virol

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The host intrinsic innate immune system drives antiviral defenses and viral restriction, which includes the production of soluble factors, such as type I and III interferon (IFN), and activation of restriction factors, including SAMHD1, a deoxynucleoside triphosphohydrolase. Interferon-stimulated gene 15 (ISG15)-specific ubiquitin-like protease 43 (USP18) abrogates IFN signaling pathways. The cyclin-dependent kinase inhibitor p21 (CIP1/WAF1), which is involved in the differentiation and maturation of monocytes, inhibits human immunodeficiency virus type 1 (HIV-1) in macrophages and dendritic cells. p21 inhibition of HIV-1 replication is thought to occur at the reverse transcription step, likely by suppressing cellular deoxynucleoside triphosphate (dNTP) biosynthesis and increasing the amount of antivirally active form of SAMHD1. SAMHD1 strongly inhibits HIV-1 replication in myeloid and resting CD4 T cells. Here, we studied how USP18 influences HIV-1 replication in human myeloid THP-1 cells. We found that USP18 has the novel ability to inhibit the antiviral function of p21 in differentiated THP-1 cells. USP18 enhanced reverse transcription of HIV-1 by downregulating p21 expression and upregulating intracellular dNTP levels. p21 downregulation by USP18 was associated with the active form of SAMHD1, phosphorylated at T592. USP18 formed a complex with the E3 ubiquitin ligase recognition factor SKP2 (S-phase kinase associated protein 2) and SAMHD1. CRISPR-Cas9 knockout of USP18 increased p21 protein expression and blocked HIV-1 replication. Overall, we propose USP18 as a regulator of p21 antiviral function in differentiated myeloid THP-1 cells. Macrophages and dendritic cells are usually the first point of contact with pathogens, including lentiviruses. Host restriction factors, including SAMHD1, mediate the innate immune response against these viruses. However, HIV-1 has evolved to circumvent the innate immune response and establishes disseminated infection. The cyclin-dependent kinase inhibitor p21, which is involved in differentiation and maturation of monocytes, blocks HIV-1 replication at the reverse transcription step. p21 is thought to suppress key enzymes involved in dNTP biosynthesis and activates SAMHD1 antiviral function. We report here that the human USP18 protein is a novel factor potentially contributing to HIV replication by blocking the antiviral function of p21 in differentiated human myeloid cells. USP18 downregulates p21 protein expression, which correlates with upregulated intracellular dNTP levels and the antiviral inactive form of SAMHD1. Depletion of USP18 stabilizes p21 protein expression, which correlates with dephosphorylated SAMHD1 and a block to HIV-1 replication.

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Interferon but not MxB inhibits foamy retroviruses

Cited by 24 publications

References 78 publications

Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway

Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway

Determinants of FIV and HIV Vif sensitivity of feline APOBEC3 restriction factors

USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1

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