Identification of an HIV-1 replication inhibitor which rescues host restriction factor APOBEC3G in Vif–APOBEC3G complex

Zhang, Shaoyang; Li, Zhong; Chen, Bing; Pan, Ting; Zhang, Xue; Liang, Liting; Li, Qianwen; Zhang, Ziying; Chen, Hui; Zhou, Jie; Luo, Haihua; Zhang, Hui; Bai, Chujie

doi:10.1016/j.antiviral.2015.07.009

Cited by 25 publications

(21 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As Vif is required for viral replication both in cell culture and in vivo , inhibition of Vif is an attractive strategy to restore the restrictive function of A3 family members and in turn cripple HIV infection. We and others have demonstrated that pharmacological inhibition of Vif unleashes the restriction potential of A3 family members [ 15 – 20 ]; however, the targets of these studies are either unknown or are host proteins required for Vif function. Although these studies demonstrate the effectiveness of antagonizing Vif to counteract HIV, targeting host factors may result in undesirable pleiotropic, off-target effects.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The first reported Vif small-molecule inhibitor, RN-18, was a Vif–A3G interaction inhibitor that inhibited HIV-1 in nonpermissive cells [ 33 , 48 ]. Several inhibitors targeting the Vif–A3G interaction have been reported in the years following the discovery RN-18, and their mechanisms of action were associated with the A3G-Vif-CBF-β-CUL5-ELOB-ELOC complex [ 31 , 35 , 49 , 50 ]. Vif–ELOC interaction is also a target of anti-HIV compounds, and compounds that could inhibit Vif–ELOC interaction have been designed.…”

Section: Discussionmentioning

confidence: 99%

“…Vif exploits the Elongin C/B (ELOC/B), Cullin 5 (CUL5), and CBF-β complex to induce A3G ubiquitination and proteasome degradation [ 23 , 25 , 26 , 27 , 28 , 29 ]. Following studies of the A3G-Vif-CBF-β-CUL5-ELOB-ELOC complex, inhibitors that target the Vif–A3G interaction have been designed to protect A3G from Vif-mediated degradation [ 30 , 31 , 32 , 33 , 34 , 35 ]. Meanwhile, regulation of A3G expression has been investigated for several years.…”

Section: Introductionmentioning

confidence: 99%

Anti-HIV Activities and Mechanism of 12-O-Tricosanoylphorbol-20-acetate, a Novel Phorbol Ester from Ostodes katharinae

et al. 2017

View full text Add to dashboard Cite

APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 μM to 7.987 μM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.

show abstract

“…pcDNA3.1-A3G-HA, pcDNA3.1-GFP-HA, pcDNA3.1-MOV10-FLAG, pcDNA3.1-MOV10-HA, pcDNA3.1-rMOV10-FLAG, pcDNA3.1-MOV10-DEAG-mutant-HA, pcDNA3.1-MOV10-DEAG-mutant-FLAG and pcDNA3.1-Ub-FLAG were constructed as described previously [ 20 , 32 , 59 ]. pcDNA3.1-Vif-HA, pcDNA3.1-Vif-FLAG, pcDNA3.1-ElonginB-FLAG, pcDNA3.1-Cullin 5-FLAG, pcDNA3.1-CBF-β-FLAG, and were constructed by our lab [ 60 ]. HA or FLAG epitope tagged codon-optimized HIV-1 vif was constructed by chemically-synthesis of DNA fragment and subcloned into pcDNA3.1.…”

Section: Methodsmentioning

confidence: 99%

Moloney leukemia virus 10 (MOV10) inhibits the degradation of APOBEC3G through interference with the Vif-mediated ubiquitin–proteasome pathway

Chen

et al. 2017

Retrovirology

Self Cite

View full text Add to dashboard Cite

BackgroundMOV10 protein has ATP-dependent 5′–3′ RNA helicase activity and belongs to the UPF1p superfamily. It can inhibit human immunodeficiency virus type 1 (HIV-1) replication at multiple stages and interact with apolipoprotein-B-mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G), a member of the cytidine deaminase family that exerts potent inhibitory effects against HIV-1 infection. However, HIV-1-encoded virion infectivity factor (Vif) protein specifically mediates the degradation of A3G via the ubiquitin–proteasome system (UPS).ResultsWe demonstrate that MOV10 counteracts Vif-mediated degradation of A3G by inhibiting the assembly of the Vif-CBF-β-Cullin 5-ElonginB-ElonginC complex. Through interference with UPS, MOV10 enhances the level of A3G in HIV-1-infected cells and virions, and synergistically inhibits the replication and infectivity of HIV-1. In addition, the DEAG-box of MOV10 is required for inhibition of Vif-mediated A3G degradation as the DEAG-box mutant significantly loses this ability.ConclusionsOur results demonstrate a novel mechanism involved in the anti-HIV-1 function of MOV10. Given that both MOV10 and A3G belong to the interferon antiviral system, their synergistic inhibition of HIV-1 suggests that these proteins may play complicated roles in antiviral functions.

show abstract

Identification of an HIV-1 replication inhibitor which rescues host restriction factor APOBEC3G in Vif–APOBEC3G complex

Cited by 25 publications

References 35 publications

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

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

Anti-HIV Activities and Mechanism of 12-O-Tricosanoylphorbol-20-acetate, a Novel Phorbol Ester from Ostodes katharinae

Moloney leukemia virus 10 (MOV10) inhibits the degradation of APOBEC3G through interference with the Vif-mediated ubiquitin–proteasome pathway

Contact Info

Product

Resources

About