Evolutionary Paradigms from Ancient and Ongoing Conflicts between the Lentiviral Vif Protein and Mammalian APOBEC3 Enzymes

Harris, Reuben S.; Anderson, Brett D.

doi:10.1371/journal.ppat.1005958

Cited by 22 publications

(17 citation statements)

References 27 publications

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“…The E2 ubiquitin-conjugating enzyme bound to the flexible Rbx2 component in the NEDD8 activated E3 ligase 48 potentially allows ubiquitination of multiple positions on A3F, as well as the bound Vif molecule 49 . This advance provides critical insights into the molecular interactions enabling the viral evasion of a major host defense, which is also conserved between other known lentiviruses and their hosts 50 . Furthermore, it has been found that HIV-1 can evade A3G, but not A3F restriction in the absence of Vif 51,52 , highlighting that the Vif-A3F interaction is essential for HIV-1 survival in cells.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of antagonism of human APOBEC3F by HIV-1 Vif

Desimmie

Nguyen

et al. 2019

Nat Struct Mol Biol

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HIV-1 Vif promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of HIV-1 replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and its cellular cofactor CBFβ, at 3.9 Å resolution. The structure shows that Vif and CBFβ form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFβ beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Discussionmentioning

confidence: 99%

Structural basis of antagonism of human APOBEC3F by HIV-1 Vif

Desimmie

Nguyen

et al. 2019

Nat Struct Mol Biol

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“…SIVcpz originated from the cross-species transmission and recombination of three different SIVs [ 5 , 6 ]. After lentiviral transmission to a new host that differs in one or many A3 proteins, Vif adaptation is expected at the interface of both proteins [ 25 , 51 ]. In our study, all tested SIVcpz Vifs had the ability to counteract cpzA3Hs (Figs 2 and 7 ).…”

Section: Discussionmentioning

confidence: 99%

Stably expressed APOBEC3H forms a barrier for cross-species transmission of simian immunodeficiency virus of chimpanzee to humans

Zhang

Manuel

et al. 2017

PLoS Pathog

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APOBEC3s (A3s) are potent restriction factors of human immunodeficiency virus type 1/simian immunodeficiency viruses (HIV-1/SIV), and can repress cross-species transmissions of lentiviruses. HIV-1 originated from a zoonotic infection of SIV of chimpanzee (SIVcpz) to humans. However, the impact of human A3s on the replication of SIVcpz remains unclear. By using novel SIVcpz reporter viruses, we identified that human APOBEC3B (A3B) and APOBEC3H (A3H) haplotype II strongly reduced the infectivity of SIVcpz, because both of them are resistant to SIVcpz Vifs. We further demonstrated that human A3H inhibited SIVcpz by deaminase dependent as well independent mechanisms. In addition, other stably expressed human A3H haplotypes and splice variants showed strong antiviral activity against SIVcpz. Moreover, most SIV and HIV lineage Vif proteins could degrade chimpanzee A3H, but no Vifs from SIVcpz and SIV of gorilla (SIVgor) lineages antagonized human A3H haplotype II. Expression of human A3H hapII in human T cells efficiently blocked the spreading replication of SIVcpz. The spreading replication of SIVcpz was also restricted by stable A3H in human PBMCs. Thus, we speculate that stably expressed human A3H protects humans against the cross-species transmission of SIVcpz and that SIVcpz spillover to humans may have started in individuals that harbor haplotypes of unstable A3H proteins.

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“…Third, Vif engages multiple A3 proteins (A3D/A3F, A3G, and A3H) through distinct binding surfaces. Lastly, it is becoming apparent that Vif antagonizes A3 proteins through multiple mechanisms including ubiquitin-mediated proteolysis as well as downregulating A3 at the transcriptional level by modulating the cellular RUNX transcription pathway [ 21 , 22 ]. Therefore, it is important to have a comprehensive understanding of Vif-mediated A3 neutralization to develop therapeutic strategies that unleash the innate immunity provided by A3 family members.…”

Section: Introductionmentioning

confidence: 99%

Fab-based inhibitors reveal ubiquitin independent functions for HIV Vif neutralization of APOBEC3 restriction factors

et al. 2018

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The lentiviral protein Viral Infectivity Factor (Vif) counteracts the antiviral effects of host APOBEC3 (A3) proteins and contributes to persistent HIV infection. Vif targets A3 restriction factors for ubiquitination and proteasomal degradation by recruiting them to a multi-protein ubiquitin E3 ligase complex. Here, we describe a degradation-independent mechanism of Vif-mediated antagonism that was revealed through detailed structure-function studies of antibody antigen-binding fragments (Fabs) to the Vif complex. Two Fabs were found to inhibit Vif-mediated A3 neutralization through distinct mechanisms: shielding A3 from ubiquitin transfer and blocking Vif E3 assembly. Combined biochemical, cell biological and structural studies reveal that disruption of Vif E3 assembly inhibited A3 ubiquitination but was not sufficient to restore its packaging into viral particles and antiviral activity. These observations establish that Vif can neutralize A3 family members in a degradation-independent manner. Additionally, this work highlights the potential of Fabs as functional probes, and illuminates how Vif uses a multi-pronged approach involving both degradation dependent and independent mechanisms to suppress A3 innate immunity.

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Evolutionary Paradigms from Ancient and Ongoing Conflicts between the Lentiviral Vif Protein and Mammalian APOBEC3 Enzymes

Cited by 22 publications

References 27 publications

Structural basis of antagonism of human APOBEC3F by HIV-1 Vif

Structural basis of antagonism of human APOBEC3F by HIV-1 Vif

Stably expressed APOBEC3H forms a barrier for cross-species transmission of simian immunodeficiency virus of chimpanzee to humans

Fab-based inhibitors reveal ubiquitin independent functions for HIV Vif neutralization of APOBEC3 restriction factors

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