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Genome Editing pp 161–186Cite as

Using Engineered Nucleases to Create HIV-Resistant Cells

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB))

Abstract

HIV-1/AIDS is often considered a priority disease in the development of genetic and cell based therapies because of the high burden imposed by current treatments, which require life-long adherence to antiretroviral drug regimens. Engineered nucleases have the capability to either disrupt a specific gene, or to promote precise gene edits or additions at the targeted gene. As one application for the gene disruption capabilities of the nucleases, HIV-1 infection provides an exceptional target in the CCR5 gene. This is the most commonly used entry co-receptor through which the virus enters into CD4+ T cells. Importantly, the loss of CCR5 is expected to be well-tolerated, since a relatively high percentage of individuals are naturally homozygous for a defective CCR5 allele. As a result, CCR5 disruption by zinc finger nuclease treatment of autologous T cells was the first-in-man use of engineered nucleases. Future applications to refine this therapy may include disrupting CCR5 in precursor hematopoietic stem cells, the additional disruption of the alternate HIV-1 co-receptor, CXCR4, in T cells, and the addition of other anti-HIV genes at a disrupted CCR5 locus to provide a combinatorial therapy. Finally, the gene disrupting actions of engineered nucleases could also be harnessed to inactivate the integrated HIV-1 genomes that persist in patients’ cells despite drug therapy, and which thereby prevent the complete eradication of the virus by drug treatments.

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Acknowledgements

We gratefully acknowledge the expertise of our collaborators at Sangamo BioSciences, including Michael Holmes, Jianbin Wang and Philip Gregory, and thank Liz Wolffe for her help compiling Table 1. This work was supported by the James B. Pendleton Charitable Trust, NIH grants HL073104, AI110149 and HL129902, and the California HIV/AIDS Research Program grant ID12-USC-245.

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Authors and Affiliations

  1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR502, Los Angeles, CA, 90033, USA

    George Nicholas Llewellyn Ph.D., Colin M. Exline Ph.D., Nathalia Holt Ph.D. & Paula M. Cannon Ph.D.

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  1. George Nicholas Llewellyn Ph.D.
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  2. Colin M. Exline Ph.D.
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  3. Nathalia Holt Ph.D.
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  4. Paula M. Cannon Ph.D.
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Correspondence to Paula M. Cannon Ph.D. .

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Editors and Affiliations

  1. Inst for Cell & Gene Therapy, Universitaetsklinikum Freiburg, Freiburg, Baden-Württemberg, Germany

    Toni Cathomen

  2. University of North Carolina, Chapel Hill, North Carolina, USA

    Matthew Hirsch

  3. Stanford Medical School, Palo Alto, California, USA

    Matthew Porteus

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© 2016 American Society of Gene and Cell Therapy

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Llewellyn, G.N., Exline, C.M., Holt, N., Cannon, P.M. (2016). Using Engineered Nucleases to Create HIV-Resistant Cells. In: Cathomen, T., Hirsch, M., Porteus, M. (eds) Genome Editing. Advances in Experimental Medicine and Biology(). Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3509-3_10

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