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Journal article
Broad-Spectrum and Personalized Guide RNAs for CRISPR/Cas9 HIV-1 Therapeutics
AIDS research and human retroviruses, v 34(11), pp 95-960
01 Nov 2018
PMCID: PMC6238604
PMID: 29968495
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system has been used to excise the HIV-1 proviral genome from latently infected cells, potentially offering a cure for HIV-infected patients. Recent studies have shown that most published HIV-1 guide RNAs (gRNAs) do not account for the diverse viral quasispecies within or among patients, which continue to diversify with time even in long-term antiretroviral therapy (ART)-suppressed patients. Given this observation, proviral genomes were deep sequenced from 23 HIV-1-infected patients in the Drexel Medicine CNS AIDS Research and Eradication Study cohort at two different visits. Based on the spectrum of integrated proviral DNA polymorphisms observed, three gRNA design strategies were explored: based on the patient's own HIV-1 sequences (personalized), based on consensus sequences from a large sample of patients [broad-spectrum (BS)], or a combination of both approaches. Using a bioinformatic algorithm, the personalized gRNA design was predicted to cut 46 of 48 patient samples at 90% efficiency, whereas the top 4 BS gRNAs (BS4) were predicted to excise provirus from 44 of 48 patient samples with 90% efficiency. Using a mixed design with the top three BS gRNAs plus one personalized gRNA (BS3 + PS1) resulted in predicted excision of provirus from 45 of 48 patient samples with 90% efficiency. In summary, these studies used an algorithmic design strategy to identify potential BS gRNAs to target a spectrum of HIV-1 long teriminal repeat (LTR) quasispecies for use with a small HIV-1-infected population. This approach should advance CRISPR/Cas9 excision technology taking into account the extensive molecular heterogeneity of HIV-1 that persists
in situ
after prolonged ART.
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Details
- Title
- Broad-Spectrum and Personalized Guide RNAs for CRISPR/Cas9 HIV-1 Therapeutics
- Creators
- Will Dampier - Drexel UniversityNeil T. Sullivan - Drexel UniversityJoshua Chang Mell - Drexel UniversityVanessa Pirrone - Drexel UniversityGarth D. Ehrlich - Drexel UniversityCheng-Han Chung - Drexel UniversityAlexander G. Allen - Drexel UniversityMathew DeSimone - Drexel UniversityWen Zhong - Drexel UniversityKatherine Kercher - Drexel UniversityShendra Passic - Drexel UniversityJean W. Williams - Drexel UniversityZsofia Szep - Drexel UniversityKamel Khalili - Temple UniversityJeffrey M. Jacobson - Temple UniversityMichael R. Nonnemacher - Drexel UniversityBrian Wigdahl - Drexel University
- Publication Details
- AIDS research and human retroviruses, v 34(11), pp 95-960
- Publisher
- Mary Ann Liebert, Inc., publishers
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Infectious Diseases (and HIV Medicine)
- Web of Science ID
- WOS:000449052500009
- Scopus ID
- 2-s2.0-85056055516
- Other Identifier
- 991019168462104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Infectious Diseases
- Virology