Evidence map›Paper›PMID 30808702›Full record

ArticlemBio2019

HIV-1 Escape from Small-Molecule Antagonism of Vif.

Mark Sharkey, Natalia Sharova, Idrees Mohammed, Sarah E Huff, Indrasena Reddy Kummetha, Gatikrushna Singh, Tariq M Rana, Mario Stevenson

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in mBio, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
1.0field-weighted citation impact, top 28% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 16 citations in OpenAlex.

  1. Article
  2. APOBECs: Our fickle friends?PLoS pathogens · 2023
    Article
  3. Review
  4. Review
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 1 country.

Mark SharkeyDepartment of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Natalia SharovaDepartment of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Idrees MohammedDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
Sarah E HuffDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
Indrasena Reddy KummethaDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
Gatikrushna SinghDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
Tariq M RanaDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA trana@ucsd.edu mstevenson@med.miami.edu.
Mario StevensonDepartment of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA trana@ucsd.edu mstevenson@med.miami.edu.
University of California, San Diego · USUniversity of Miami · US

Funding

University of Miami Developmental Center for AIDS Research (D-CFAR)P30AI073961 · NIAID · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI ALLAN E RODRIGUEZ · 2007 to 2026
$33.8M
Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanismsU19AI096109 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PALMER, SARAH ELIZABETH · 2011 to 2015
$29.5M
Vif Antagonism: Lead Discovery and SAR - Project 1P01MH100942 · NIMH · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI STEVENSON, MARIO · 2013 to 2017
$6.0M
The role of myeloid cells in viral replication, persistence and neuroinvasionR01MH093306 · NIMH · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI STEVENSON, MARIO · 2011 to 2015
$1.8M
NIAID NIH HHS P30 AI073961NIAID NIH HHS U19 AI096109NIMH NIH HHS P01 MH100942NIMH NIH HHS R01 MH093306
6 · The paper itself

Abstract

The HIV-1 accessory protein Vif, which counteracts the antiviral action of the DNA-editing cytidine deaminase APOBEC3G (A3G), is an attractive and yet unexploited therapeutic target. Vif reduces the virion incorporation of A3G by targeting the restriction factor for proteasomal degradation in the virus-producing cell. Compounds that inhibit Vif-mediated degradation of A3G in cells targeted by HIV-1 would represent a novel antiviral therapeutic. We previously described small molecules with activity consistent with Vif antagonism. In this study, we derived inhibitor escape HIV-1 variants to characterize the mechanism by which these novel agents inhibit virus replication. Here we show that resistance to these agents is dependent on an amino acid substitution in Vif (V142I) and on a point mutation that likely upregulates transcription by modifying the lymphocyte enhancing factor 1 (LEF-1) binding site. Molecular modeling demonstrated a docking site in the Vif-Elongin C complex that is disrupted by these inhibitors. This docking site is lost when Vif acquires the V142I mutation that leads to inhibitor resistance. Competitive fitness experiments indicated that the V142I Vif and LEF-1 binding site mutations created a virus that is better adapted to growing in the presence of A3G than the wild-type virus.

Indexed as

Drug Resistance, ViralMutation, MissenseAmino Acid SubstitutionAntiviral AgentsAPOBEC-3G DeaminaseBinding SitesCell LineHIV-1HumansLymphoid Enhancer-Binding Factor 1Molecular Docking SimulationPoint Mutationvif Gene Products, Human Immunodeficiency VirusVirus ReplicationAntiviral AgentsAPOBEC-3G DeaminaseAPOBEC3G protein, humanLEF1 protein, humanLymphoid Enhancer-Binding Factor 1vif Gene Products, Human Immunodeficiency Virusvif protein, Human immunodeficiency virus 1antiretroviral agentsantiretroviral resistanceAPOBECHIV-1Vif

Identifiers

PMID30808702
PMCPMC6391917
OpenAlexW2917661878

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.