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Editing CCR5: A Novel Approach to HIV Gene Therapy

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Gene Therapy for HIV and Chronic Infections

Part of the book series: Advances in Experimental Medicine and Biology ((ASGCT,volume 848))

Abstract

Acquired immunodeficiency syndrome (AIDS) is a life-threatening disorder caused by infection of individuals with the human immunodeficiency virus (HIV). Entry of HIV-1 into target cells depends on the presence of two surface proteins on the cell membrane: CD4, which serves as the main receptor, and either CCR5 or CXCR4 as a co-receptor. A limited number of people harbor a genomic 32-bp deletion in the CCR5 gene (CCR5∆32), leading to expression of a truncated gene product that provides resistance to HIV-1 infection in individuals homozygous for this mutation. Moreover, allogeneic hematopoietic stem cell (HSC) transplantation with CCR5∆32 donor cells seems to confer HIV-1 resistance to the recipient as well. However, since Δ32 donors are scarce and allogeneic HSC transplantation is not exempt from risks, the development of gene editing tools to knockout CCR5 in the genome of autologous cells is highly warranted. Targeted gene editing can be accomplished with designer nucleases, which essentially are engineered restriction enzymes that can be designed to cleave DNA at specific sites. During repair of these breaks, the cellular repair pathway often introduces small mutations at the break site, which makes it possible to disrupt the ability of the targeted locus to express a functional protein, in this case CCR5. Here, we review the current promise and limitations of CCR5 gene editing with engineered nucleases, including factors affecting the efficiency of gene disruption and potential off-target effects.

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Authors and Affiliations

  1. Institute for Cell and Gene Therapy, University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany

    Tatjana I. Cornu Ph.D., Claudio Mussolino Ph.D. & Toni Cathomen Ph.D.

  2. Institute for Cell and Gene Therapy and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany

    Kristie Bloom Ph.D.

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  1. Tatjana I. Cornu Ph.D.
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  2. Claudio Mussolino Ph.D.
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  3. Kristie Bloom Ph.D.
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  4. Toni Cathomen Ph.D.
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Correspondence to Toni Cathomen Ph.D. .

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Editors and Affiliations

  1. University of Amsterdam, Amsterdam, The Netherlands

    Ben Berkhout

  2. The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hildegund C.J. Ertl

  3. University of the Witwatersrand, Johannesburg, South Africa

    Marc S. Weinberg

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Cornu, T.I., Mussolino, C., Bloom, K., Cathomen, T. (2015). Editing CCR5: A Novel Approach to HIV Gene Therapy. In: Berkhout, B., Ertl, H., Weinberg, M. (eds) Gene Therapy for HIV and Chronic Infections. Advances in Experimental Medicine and Biology(), vol 848. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2432-5_6

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