Evidence map›Paper›PMID 34233649›Full record

ArticleBMC infectious diseases2021

Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening.

Simon X M Dong, Frederick S Vizeacoumar, Kalpana K Bhanumathy, Nezeka Alli, Cristina Gonzalez-Lopez, Niranjala Gajanayaka, Ramon Caballero, Hamza Ali, Andrew Freywald, Edana Cassol and 3 more

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

Article in BMC infectious diseases, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
0.1field-weighted citation impact, top 56% 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

0 citing papers in PubMed, 2 citations in OpenAlex.

No citing paper in PubMed yet.

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

13 authors at 5 institutions in 1 country.

Simon X M DongApoptosis Research Center, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Frederick S VizeacoumarDepartment of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Kalpana K BhanumathyDepartment of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Nezeka AlliDepartment of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Cristina Gonzalez-LopezCancer Research, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK, Canada.
Niranjala GajanayakaApoptosis Research Center, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Ramon CaballeroApoptosis Research Center, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Hamza AliApoptosis Research Center, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Andrew FreywaldDepartment of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Edana CassolDepartment of Health Sciences, Carleton University, Ottawa, ON, Canada.
Jonathan B AngelDepartment of Medicine, the Ottawa Health Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Franco J VizeacoumarDepartment of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada. franco.vizeacoumar@usask.ca.
Ashok KumarApoptosis Research Center, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. akumar@uottawa.ca.
University of Saskatchewan · CAUniversity of Ottawa · CAChildren's Hospital of Eastern Ontario · CACarleton University · CASaskatchewan Cancer Agency · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundMacrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages.

methodsWe applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student's t-test from at least four independent experiments.

resultsWe validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production.

conclusionsWe have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

Indexed as

Green Fluorescent ProteinsHIV InfectionsMacrophagesRNA, Small InterferingApoptosisCD4-Positive T-LymphocytesGenome-Wide Association StudyHIV-1HumansT-Lymphocytesenhanced green fluorescent proteinGreen Fluorescent ProteinsRNA, Small Interfering90K lentivirus shRNA pool technologyAIDSApoptosisGenome-wide screeningHIV reservoirMacrophagesSelective killing

Identifiers

PMID34233649
PMCPMC8261936
OpenAlexW3181346529

What Socratic 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 Socratic graph.