Genome editing strategies: potential tools for eradicating HIV-1/AIDS

Abstract

Current therapy for controlling human immunodeficiency virus (HIV-1) infection and preventing acquired immunodeficiency syndrome (AIDS) progression has profoundly decreased viral replication in cells susceptible to HIV-1 infection, but it does not eliminate the low level of viral replication in latently infected cells, which contain integrated copies of HIV-1 proviral DNA. There is an urgent need for the development of HIV-1 genome eradication strategies that will lead to a permanent or “sterile” cure of HIV-1/AIDS. In the past few years, novel nuclease-initiated genome editing tools have been developing rapidly, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas9 system. These surgical knives, which can excise any genome, provide a great opportunity to eradicate the HIV-1 genome by targeting highly conserved regions of the HIV-1 long terminal repeats or essential viral genes. Given the time consuming and costly engineering of target-specific ZFNs and TALENs, the RNA-guided endonuclease Cas9 technology has emerged as a simpler and more versatile technology to allow permanent removal of integrated HIV-1 proviral DNA in eukaryotic cells, and hopefully animal models or human patients. The major unmet challenges of this approach at present include inefficient nuclease gene delivery, potential off-target cleavage, and cell-specific genome targeting. Nanoparticle or lentivirus-mediated delivery of next generation Cas9 technologies including nickase or RNA-guided FokI nuclease (RFN) will further improve the potential for genome editing to become a promising approach for curing HIV-1/AIDS.

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Acknowledgments

The authors thank past and present members of the Department of Neuroscience and the Center for Neurovirology. We also thank C. Papaleo for editorial assistance. This work was supported by R01NS087971 (W.H., K.K.) and P30MH092177 (K.K.).

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The authors declare that they have no conflict of interests.

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Correspondence to Kamel Khalili or Wenhui Hu.

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Khalili, K., Kaminski, R., Gordon, J. et al. Genome editing strategies: potential tools for eradicating HIV-1/AIDS. J. Neurovirol. 21, 310–321 (2015). https://doi.org/10.1007/s13365-014-0308-9

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Keywords

  • Genome editing
  • CRISPR/Cas9
  • HIV-1 integration
  • Latent reservoir
  • Cure
  • Animal models