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Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection

Antiretroviral therapy has prolonged the lives of people living with human immunodeficiency virus type 1 (HIV-1), transforming the disease into one that can be controlled with lifelong therapy. The search for an HIV-1 vaccine has plagued researchers for more than three decades with little to no succ...

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Autores principales: Allen, Alexander G., Chung, Cheng-Han, Atkins, Andrew, Dampier, Will, Khalili, Kamel, Nonnemacher, Michael R., Wigdahl, Brian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304358/
https://www.ncbi.nlm.nih.gov/pubmed/30619107
http://dx.doi.org/10.3389/fmicb.2018.02940
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author Allen, Alexander G.
Chung, Cheng-Han
Atkins, Andrew
Dampier, Will
Khalili, Kamel
Nonnemacher, Michael R.
Wigdahl, Brian
author_facet Allen, Alexander G.
Chung, Cheng-Han
Atkins, Andrew
Dampier, Will
Khalili, Kamel
Nonnemacher, Michael R.
Wigdahl, Brian
author_sort Allen, Alexander G.
collection PubMed
description Antiretroviral therapy has prolonged the lives of people living with human immunodeficiency virus type 1 (HIV-1), transforming the disease into one that can be controlled with lifelong therapy. The search for an HIV-1 vaccine has plagued researchers for more than three decades with little to no success from clinical trials. Due to these failures, scientists have turned to alternative methods to develop next generation therapeutics that could allow patients to live with HIV-1 without the need for daily medication. One method that has been proposed has involved the use of a number of powerful gene editing tools; Zinc Finger Nucleases (ZFN), Transcription Activator–like effector nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to edit the co-receptors (CCR5 or CXCR4) required for HIV-1 to infect susceptible target cells efficiently. Initial safety studies in patients have shown that editing the CCR5 locus is safe. More in depth in vitro studies have shown that editing the CCR5 locus was able to inhibit infection from CCR5-utilizing virus, but CXCR4-utilizing virus was still able to infect cells. Additional research efforts were then aimed at editing the CXCR4 locus, but this came with other safety concerns. However, in vitro studies have since confirmed that CXCR4 can be edited without killing cells and can confer resistance to CXCR4-utilizing HIV-1. Utilizing these powerful new gene editing technologies in concert could confer cellular resistance to HIV-1. While the CD4, CCR5, CXCR4 axis for cell-free infection has been the most studied, there are a plethora of reports suggesting that the cell-to-cell transmission of HIV-1 is significantly more efficient. These reports also indicated that while broadly neutralizing antibodies are well suited with respect to blocking cell-free infection, cell-to-cell transmission remains refractile to this approach. In addition to stopping cell-free infection, gene editing of the HIV-1 co-receptors could block cell-to-cell transmission. This review aims to summarize what has been shown with regard to editing the co-receptors needed for HIV-1 entry and how they could impact the future of HIV-1 therapeutic and prevention strategies.
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spelling pubmed-63043582019-01-07 Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection Allen, Alexander G. Chung, Cheng-Han Atkins, Andrew Dampier, Will Khalili, Kamel Nonnemacher, Michael R. Wigdahl, Brian Front Microbiol Microbiology Antiretroviral therapy has prolonged the lives of people living with human immunodeficiency virus type 1 (HIV-1), transforming the disease into one that can be controlled with lifelong therapy. The search for an HIV-1 vaccine has plagued researchers for more than three decades with little to no success from clinical trials. Due to these failures, scientists have turned to alternative methods to develop next generation therapeutics that could allow patients to live with HIV-1 without the need for daily medication. One method that has been proposed has involved the use of a number of powerful gene editing tools; Zinc Finger Nucleases (ZFN), Transcription Activator–like effector nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to edit the co-receptors (CCR5 or CXCR4) required for HIV-1 to infect susceptible target cells efficiently. Initial safety studies in patients have shown that editing the CCR5 locus is safe. More in depth in vitro studies have shown that editing the CCR5 locus was able to inhibit infection from CCR5-utilizing virus, but CXCR4-utilizing virus was still able to infect cells. Additional research efforts were then aimed at editing the CXCR4 locus, but this came with other safety concerns. However, in vitro studies have since confirmed that CXCR4 can be edited without killing cells and can confer resistance to CXCR4-utilizing HIV-1. Utilizing these powerful new gene editing technologies in concert could confer cellular resistance to HIV-1. While the CD4, CCR5, CXCR4 axis for cell-free infection has been the most studied, there are a plethora of reports suggesting that the cell-to-cell transmission of HIV-1 is significantly more efficient. These reports also indicated that while broadly neutralizing antibodies are well suited with respect to blocking cell-free infection, cell-to-cell transmission remains refractile to this approach. In addition to stopping cell-free infection, gene editing of the HIV-1 co-receptors could block cell-to-cell transmission. This review aims to summarize what has been shown with regard to editing the co-receptors needed for HIV-1 entry and how they could impact the future of HIV-1 therapeutic and prevention strategies. Frontiers Media S.A. 2018-12-17 /pmc/articles/PMC6304358/ /pubmed/30619107 http://dx.doi.org/10.3389/fmicb.2018.02940 Text en Copyright © 2018 Allen, Chung, Atkins, Dampier, Khalili, Nonnemacher and Wigdahl. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Allen, Alexander G.
Chung, Cheng-Han
Atkins, Andrew
Dampier, Will
Khalili, Kamel
Nonnemacher, Michael R.
Wigdahl, Brian
Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
title Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
title_full Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
title_fullStr Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
title_full_unstemmed Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
title_short Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection
title_sort gene editing of hiv-1 co-receptors to prevent and/or cure virus infection
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304358/
https://www.ncbi.nlm.nih.gov/pubmed/30619107
http://dx.doi.org/10.3389/fmicb.2018.02940
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