CRISPR-Cas9 Can Inhibit HIV-1 Replication but NHEJ Repair Facilitates Virus Escape

Wang, Gang; Zhao, Na; Berkhout, Ben; Das, Atze T.

doi:10.1038/mt.2016.24

Cited by 198 publications

(264 citation statements)

References 27 publications

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“…However, if only single gRNA is used for a single target site, it is possible to generate InDels where the mutated gene can be changed in such a way as to allow the virus to replicate but yet no longer be susceptible to cleavage by Cas9 because its mutated sequence is now different to the Cas9/gRNA target sequence, i.e., an “escape mutant”. (Wang et al, 2016a, 2016e; Khalili et al, 2017). Thus when designing any gene editing strategy against HIV, it is essential to consider the possibility of escape mutants arising (White et al, 2016).…”

Section: Recent Applications Of Crisprmentioning

confidence: 99%

CRISPR Editing Technology in Biological and Biomedical Investigation

White

Kaminski

Young

et al. 2017

J of Cellular Biochemistry

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The CRISPR or clustered regularly interspaced short palindromic repeats system is currently the most advanced approach to genome editing and is notable for providing an unprecedented degree of specificity, effectiveness and versatility in genetic manipulation. CRISPR evolved as a prokaryotic immune system to confer provide an acquired immunity and resistance to foreign genetic elements such as bacteriophages. It has recently been developed into a tool for the specific targeting of nucleotide sequences within complex eukaryotic genomes for the purpose of genetic manipulation. The power of CRISPR lies in its simplicity and ease of use, its flexibility to be targeted to any given nucleotide sequence by the choice of an easily synthesized guide RNA, and its ready ability to continue to undergo technical improvements. Applications for CRISPR are numerous including creation of novel transgenic cell animals for research, high-throughput screening of gene function, potential clinical gene therapy and nongene-editing approaches such as modulating gene activity and fluorescent tagging. In this prospect article, we will describe the salient features of the CRISPR system with an emphasis on important drawbacks and considerations with respect to eliminating off-target events and obtaining efficient CRISPR delivery. We will discuss recent technical developments to the system and we will illustrate some of the most recent applications with an emphasis on approaches to eliminate human viruses including HIV-1, JCV and HSV-1 and prospects for the future.

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Section: Recent Applications Of Crisprmentioning

confidence: 99%

CRISPR Editing Technology in Biological and Biomedical Investigation

White

Kaminski

Young

et al. 2017

J of Cellular Biochemistry

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“…Indeed, one study identified a mutational insertion in a highly conserved region of pol that provided resistance to subsequent endonuclease cleavage but did not lethally mutate the virus [69]. In another study, virus escaped CRISPR/Cas9 targeting of several conserved regions of the HIV genome [70]. These results highlight the need for careful choice of target and suggest that simultaneous targeting of multiple essential genes may be necessary.…”

Section: Targeting the Hiv Genome Directlymentioning

confidence: 99%

Cell and gene therapy strategies to eradicate HIV reservoirs

Spragg

Feelixge

Jerome

2016

Current Opinion in HIV and AIDS

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Purpose of review Highly active antiretroviral treatment has dramatically improved prognosis for people living with HIV by preventing AIDS-related morbidity and mortality through profound suppression of viral replication. However, a long-lived viral reservoir persists in latently infected cells that harbor replication-competent HIV genomes. If therapy is discontinued, latently infected memory cells inevitably reactivate and produce infectious virus, resulting in viral rebound. The reservoir is the biggest obstacle to a cure of HIV. Recent findings This review summarizes significant advances of the past year in the development of cellular and gene therapies for HIV cure. In particular, we highlight work done on suppression or disruption of HIV co-receptors, vectored delivery of antibodies and antibody-like molecules, T cell therapies, and HIV genome disruption. Summary A number of recent advancements in cellular and gene therapies have emerged at the forefront of HIV cure research, potentially having broad implications for the future of HIV treatment.

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“…25 Similar resistance mutants have been shown to emerge and replicate in cultures undergoing treatment with HIV-targeted Cas9. [26][27][28] Fortunately, it appears that the emergence of resistance can be successfully managed in a manner that is analogous to traditional antiviral therapy, by simultaneously targeting multiple sites within the viral genome. Although ten or more sites may be required if targeting is limited to the LTR, 22 attacking other more conserved sites elsewhere in the genome may allow fewer targets to suffice.…”

Section: Resistancementioning

confidence: 99%

Disruption or Excision of Provirus as an Approach to HIV Cure

Jerome

2016

AIDS Patient Care and STDs

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An effective approach to HIV cure will almost certainly require a combination of strategies, including some means of reducing the latent HIV reservoir. Because the integrated HIV provirus represents the major source of viral persistence and reactivation, one attractive approach is the direct targeting of provirus for disruption or excision using targeted endonucleases, such as CRISPR/Cas9, zinc finger nucleases, TAL effector nucleases, or meganucleases (homing endonucleases). This article highlights some of the challenges for successful endonuclease therapy for HIV, including optimization of enzyme activity and specificity, the possible emergence of viral resistance, and most importantly, efficient in vivo delivery of the enzymes to a sufficient portion of the latent reservoir.

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CRISPR-Cas9 Can Inhibit HIV-1 Replication but NHEJ Repair Facilitates Virus Escape

Cited by 198 publications

References 27 publications

CRISPR Editing Technology in Biological and Biomedical Investigation

CRISPR Editing Technology in Biological and Biomedical Investigation

Cell and gene therapy strategies to eradicate HIV reservoirs

Disruption or Excision of Provirus as an Approach to HIV Cure

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