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01-12-2021 | Human Immunodeficiency Virus | Research

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

Authors: 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, Jonathan B. Angel, Franco J. Vizeacoumar, Ashok Kumar

Published in: BMC Infectious Diseases | Issue 1/2021

Abstract

Background

Macrophages, 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.

Methods

We 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.

Results

We 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.

Conclusions

We 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.

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Title: Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening
Authors: 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
Jonathan B. Angel
Franco J. Vizeacoumar
Ashok Kumar
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Human Immunodeficiency Virus
Published in: BMC Infectious Diseases / Issue 1/2021
Electronic ISSN: 1471-2334
DOI: https://doi.org/10.1186/s12879-021-06346-7

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