Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Jain, Prashant; Boso, Guney; Langer, Simon; Soonthornvacharin, Stephen; Nguyen, Quy Thi Cam; Olivieri, Kevin; Portillo, Alex J.; Yoh, Sunnie M.; Pache, Lars; Chanda, Sumit K.

doi:10.1016/j.celrep.2018.01.091

Cited by 22 publications

(23 citation statements)

References 64 publications

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“…Further, a moderate level of Tetherin antagonism could be selected for if cell-to-cell transmission is enhanced by Tetherin restriction ( Gummuluru et al, 2000 ; Jolly et al, 2010 ), such as is observed for MoMLV in mice ( Liberatore et al, 2017 ). Interestingly, Vpu counteracts UBE2L6 ( Jain et al, 2018 ) which we describe as an inhibitor of both HIV-1 LAI and HIV-1 Q23.BG505 suggesting that Vpu from both viruses are unable to fully counteract UBE2L6 in IFN-treated THP-1 cells.…”

Section: Discussionmentioning

confidence: 78%

“…MxB, TRIM5alpha, UBE2L6 and IFITM1 are strong hits in both the HIV-1 LAI and the HIV-1 Q23.BG505 screens (cyan in Figure 6B ) suggesting that these ISGs inhibit a range of HIV isolates. UBE2L6 has recently been shown to inhibit HIV in an overexpression assay and is antagonized by Vpu ( Jain et al, 2018 ). In contrast, several other ISGs scored highly in the HIV-1 LAI PIKA HIV screen but not the HIV-1 Q23.BG505 screen including LGALS3BP (also known as 90K or M2BP), SAMD9L and Tetherin/BST2 (dark blue in Figure 6B ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, several other ISGs scored highly in the HIV-1 LAI PIKA HIV screen but not the HIV-1 Q23.BG505 screen including LGALS3BP (also known as 90K or M2BP), SAMD9L and Tetherin/BST2 (dark blue in Figure 6B ). UBE2L6 and 90K inhibit HIV in over-expression assays ( Jain et al, 2018 ; Lodermeyer et al, 2013 ; Wang et al, 2016 ) and SAMD9L was recently shown to be an IFN-induced restriction factor for poxviruses ( Meng et al, 2018 ). Tetherin/BST2, LGALS3BP/90K/M2BP and SAMD9L therefore show differential, strain-dependent restriction.…”

Section: Discussionmentioning

confidence: 99%

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A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

OhAinle

Helms

Vermeíre

et al. 2018

eLife

122

155

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Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced HIV restriction factors, we assembled a CRISPR sgRNA library of Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. A small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5alpha together explain the inhibitory effects of IFN on the CXCR4-tropic HIV-1 strain, HIV-1LAI, in THP-1 cells. A second screen with a CCR5-tropic primary strain, HIV-1Q23.BG505, described an overlapping, but non-identical, panel of restriction factors. Further, this screen also identifies HIV dependency factors. The ability of IFN-induced restriction factors to inhibit HIV strains to replicate in human cells suggests that these human restriction factors are incompletely antagonized.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

OhAinle

Helms

Vermeíre

et al. 2018

eLife

122

155

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“…In particular, Vif usurps a cellular RING ubiquitin ligase assembled on a Cullin 5 scaffold (CRL5) to antagonize APOBEC3 family cytidine deaminases, which are capable of inducing lethal G-to-A hypermutation in viral cDNA ( 4 ). Vpu hijacks a CRL1 E3 ubiquitin ligase complex to antagonize the CD4 receptor ( 5 ), thereby preventing superinfection, and to deplete select proteins that are involved in interferon-inducible antiviral pathways ( 6 ). Overall, how Vif and Vpu exploit cellular E3 enzymes to facilitate HIV-1 infection is relatively well understood.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Vpr Reprograms CLR4 ^DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection

Yan

Shun

Hao

et al. 2018

mBio

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HIV-1 polymerase reverse transcribes the viral RNA genome into imperfectly double-stranded proviral DNA, containing gaps and flaps, for integration into the host cell chromosome. HIV-1 reverse transcripts share characteristics with cellular DNA replication intermediates and are thought to be converted into fully double-stranded DNA by cellular postreplication DNA repair enzymes. Therefore, the finding that the HIV-1 accessory protein Vpr antagonizes select postreplication DNA repair enzymes that can process HIV-1 reverse transcripts has been surprising. Here, we show that one such Vpr-antagonized enzyme, exonuclease 1, inhibits HIV-1 replication in T cells. We identify exonuclease 1 as a member of a new class of HIV-1 restriction factors in T cells and propose that certain modes of DNA “repair” inhibit HIV-1 infection.

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“…HIV-1 Vif recruits the Cul5/Elongin ubiquitin ligase complex to target APOBEC3 for degradation [96][97][98], while Vpu downmodulates both CD4 and tetherin/BST2 by recruiting a cullin1-Skp1 ubiquitin ligase complex. Recently, it was found that HIV-1 Vpu targets additional ISGs including CD99, PLP2, and UBE2L6 for proteolytic degradation in a manner mechanistically similar to antagonism of BST2 [99][100][101][102]. HIV-1 Vpr and its Vpr/Vpx homologs in HIV-2 and SIV associate with the cullin4A-DDB1-DCAF1 complex to target multiple host factors including tet methylcytosine dioxygenase 2 (TET2) and helicase-like transcription factor (HLTF) for degradation, thus promoting virus infection [103,104].…”

Section: Counteraction Of Hiv-1 Restriction Factorsmentioning

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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Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Cited by 22 publications

References 64 publications

A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

HIV-1 Vpr Reprograms CLR4 ^DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection

Sensor Sensibility—HIV-1 and the Innate Immune Response

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Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu

Cited by 22 publications

References 64 publications

A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

HIV-1 Vpr Reprograms CLR4 DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection

Sensor Sensibility—HIV-1 and the Innate Immune Response

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HIV-1 Vpr Reprograms CLR4 ^DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection