Identification of an APOBEC3G Binding Site in Human Immunodeficiency Virus Type 1 Vif and Inhibitors of Vif-APOBEC3G Binding

Mehle, Andrew; Wilson, Heather M.; Zhang, Chengsheng; Brazier, Andrew J.; McPike, Mark P.; Pery, Erez; Gabuzda, Dana

doi:10.1128/jvi.00204-07

Cited by 94 publications

(105 citation statements)

References 43 publications

(54 reference statements)

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“…Several potential APOBEC3-Vif interaction motifs have recently been described (37,38). Our results support the validity of this putative drug target but also inform about the unintended consequences of therapies targeting this protein-protein interaction with less than absolute efficacy.…”

Section: Table 1 Summary Of Hiv-1 Drug Resistance Mutations That Ressupporting

confidence: 65%

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Cytidine deamination induced HIV-1 drug resistance

Mulder

Harari²,

Simon³

2008

Proc. Natl. Acad. Sci. U.S.A.

148

169

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The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in >40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies.hypermutation ͉ reservoir ͉ diversity ͉ reverse transcription

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Section: Table 1 Summary Of Hiv-1 Drug Resistance Mutations That Ressupporting

confidence: 65%

“…4A). (25,37,38,40). Each Vif mutation was introduced into the molecular clone HIV-1 NL4-3 and subsequently characterized.…”

Section: Genotypic and Phenotypic Characterization Of Proviruses Derivedmentioning

confidence: 99%

Cytidine deamination induced HIV-1 drug resistance

Mulder

Harari²,

Simon³

2008

Proc. Natl. Acad. Sci. U.S.A.

148

169

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“…Compound N.41 inhibited the Vif-A3G interaction by 89% when tested at 6.25 M in the TR-FRET high throughput screening assay. For comparison, P15, a 15-mer Vif peptide (residues 57-71) used as a positive control (40,46), exhibited an average inhibition of 40% at 50 M and 93.5% at 100 M. The secondary TR-FRET-based assay and counter screen assays (Fig. 1C) validated N.41 as a promising compound for subsequent follow-up evaluations.…”

Section: Resultsmentioning

confidence: 99%

“…1A) (40,46). In this assay interaction between purified GST-Vif residues 1-94 (1-94 GST-Vif), which includes A3G binding sites, and a synthetic biotinylated peptide containing A3G residues 110 -148 (bio-A3G), which includes the Vif-binding site, is detected by europium (europium-donor fluorophore)-labeled anti-GST antibodies and Streptavidin-Ulight (acceptor fluorophore).…”

Section: Resultsmentioning

confidence: 99%

“…Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay-The interaction between GST-Vif residues 1-94, which contains the A3G-binding site (mapped to residues 40 -72), and a biotinylated peptide consisting of A3G residues 110 -148 (bio-A3G) was detected using TR-FRET (40,46). europium (EU-W1024-labeled anti-GST antibody, PerkinElmer Life Sciences) and Ulight (LANCE Ultra Ulightstreptavidin, PerkinElmer Life Sciences) served as the donoraccepter pair.…”

Section: Methodsmentioning

confidence: 99%

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Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G Protein

Pery

Sheehy

Nebane

et al. 2015

Journal of Biological Chemistry

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Background:The interaction between HIV Vif protein and innate antiviral factor APOBEC3G represents a potential therapeutic target. Results: Screening for inhibitors of Vif-APOBEC3G interaction identified a small molecule, N.41, that protects APOBEC3G from Vif-mediated degradation and exhibits antiviral activity. Conclusion: N.41 is a lead for further development as an antiviral. Significance: These findings suggest new strategies for developing anti-HIV therapeutics.

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