Evidence map›Paper›PMID 31167922›Full record

ArticleJournal of virology2019

A Novel Phenotype Links HIV-1 Capsid Stability to cGAS-Mediated DNA Sensing.

Mohammad Adnan Siddiqui, Akatsuki Saito, Upul D Halambage, Damien Ferhadian, Douglas K Fischer, Ashwanth C Francis, Gregory B Melikyan, Zandrea Ambrose, Christopher Aiken, Masahiro Yamashita

Open access · bronzeAbstract read
In one paragraph

Article in Journal of virology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
3.1field-weighted citation impact, top 8% 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

32 citing papers in PubMed, 48 citations in OpenAlex.

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  8. IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus.Proceedings of the National Academy of Sciences of the United States of America · 2024
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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

10 authors at 4 institutions in 1 country.

Mohammad Adnan SiddiquiAaron Diamond AIDS Research Center, New York, New York, USA.
Akatsuki SaitoAaron Diamond AIDS Research Center, New York, New York, USA.ORCID 0000-0002-2792-4399
Upul D HalambageDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Damien FerhadianAaron Diamond AIDS Research Center, New York, New York, USA.
Douglas K FischerDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Ashwanth C FrancisDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA.
Gregory B MelikyanDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA.
Zandrea AmbroseDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.ORCID 0000-0002-8610-2766
Christopher AikenDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Masahiro YamashitaAaron Diamond AIDS Research Center, New York, New York, USA myamashi@adarc.org.ORCID 0000-0002-4482-2378
Aaron Diamond AIDS Research Center · USEmory University · USUniversity of Pittsburgh · USVanderbilt University Medical Center · US

Funding

X-Ray Core P50GM082251 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI ENGELMAN, ALAN N. · 2007 to 2018
$48.1M
Technology Development 2: MAS NMR and dynamic nuclear polarization for HIV-1 structural biologyP50AI150481 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GRONENBORN, ANGELA M. · 2019 to 2021
$14.1M
Mechanism and role of nuclear entry in HIV-1 replicationR01AI100720 · NIAID · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Masahiro Yamashita · 2012 to 2026
$6.5M
Imaging of Single HIV-1 Uncoating and Transport to the nucleusR01AI129862 · NIAID · EMORY UNIVERSITY · PI KVARATSKHELIA, MAMUKA, MELIKIAN, GREGORY B · 2017 to 2025
$5.4M
PITT AIDS RESEARCH TRAINING PROGRAMT32AI065380 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BARRATT-BOYES, SIMON M · 2005 to 2020
$3.2M
A Competition Binding Assay for Identifying Novel HIV-1 Capsid LigandsR01AI114339 · NIAID · VANDERBILT UNIVERSITY MEDICAL CENTER · PI AIKEN, CHRISTOPHER R · 2014 to 2016
$1.1M
NIAID NIH HHS P50 AI150481NIAID NIH HHS R01 AI100720NIAID NIH HHS R01 AI114339NIAID NIH HHS R01 AI129862NIAID NIH HHS T32 AI065380NIGMS NIH HHS P50 GM082251
6 · The paper itself

Abstract

The HIV-1 capsid executes essential functions that are regulated by capsid stability and host factors. In contrast to increasing knowledge on functional roles of capsid-interacting host proteins during postentry steps, less is known about capsid stability and its impact on intracellular events. Here, using the antiviral compound PF-3450074 (PF74) as a probe for capsid function, we uncovered a novel phenotype of capsid stability that has a profound effect on innate sensing of viral DNA by the DNA sensor cGAS. A single mutation, R143A, in the capsid protein conferred resistance to high concentrations of PF74, without affecting capsid binding to PF74. A cell-free assay showed that the R143A mutant partially counteracted the capsid-destabilizing activity of PF74, pointing to capsid stabilization as a resistance mechanism for the R143A mutant. In monocytic THP-1 cells, the R143A virus, but not the wild-type virus, suppressed cGAS-dependent innate immune activation. These results suggest that capsid stabilization improves the shielding of viral DNA from innate sensing. We found that a naturally occurring transmitted founder (T/F) variant shares the same properties as the R143A mutant with respect to PF74 resistance and DNA sensing. Imaging assays revealed delayed uncoating kinetics of this T/F variant and the R143A mutant. All these phenotypes of this T/F variant were controlled by a genetic polymorphism located at the trimeric interface between capsid hexamers, thus linking these capsid-dependent properties. Overall, this work functionally connects capsid stability to innate sensing of viral DNA and reveals naturally occurring phenotypic variation in HIV-1 capsid stability.

Indexed as

DNA, ViralHost-Pathogen InteractionsAmino Acid SequenceAnti-HIV AgentsCapsidCapsid ProteinsCell Line, TumorCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDisease ResistanceHIV-1HIV InfectionsHumansIndolesMutationNucleotidyltransferasesPhenylalanineAnti-HIV AgentsCapsid ProteinscGAS protein, humanCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDNA, ViralIndolesNucleotidyltransferasesPF-3450074Phenylalaninecapsidhuman immunodeficiency virus

Identifiers

PMID31167922
PMCPMC6675898
OpenAlexW2947776159

What OpenQuestion holds

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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.