Proviral HIV-genome-wide and pol-gene specific zinc finger nucleases: Usability for targeted HIV gene therapy
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BACKGROUND: Infection with HIV, which culminates in the establishment of a latent proviral reservoir, presents formidable challenges for ultimate cure. Building on the hypothesis that ex-vivo or even in-vivo abolition or disruption of HIV-gene/genome-action by target mutagenesis or excision can irreversibly abrogate HIV's innate fitness to replicate and survive, we previously identified the isoschizomeric bacteria restriction enzymes (REases) AcsI and ApoI as potent cleavers of the HIV-pol gene (11 and 9 times in HIV-1 and 2, respectively). However, both enzymes, along with others found to cleave across the entire HIV-1 genome, slice (SX) at palindromic sequences that are prevalent within the human genome and thereby pose the risk of host genome toxicity. A long-term goal in the field of R-M enzymatic therapeutics has thus been to generate synthetic restriction endonucleases with longer recognition sites limited in specificity to HIV. We aimed (i) to assemble and construct zinc finger arrays and nucleases (ZFN) with either proviral-HIV-pol gene or proviral-HIV-1 whole-genome specificity respectively, and (ii) to advance a model for pre-clinically testing lentiviral vectors (LV) that deliver and transduce either ZFN genotype. METHODS AND RESULTS: First, we computationally generated the consensus sequences of (a) 114 dsDNA-binding zinc finger (Zif) arrays (ZFAs or ZifHIV-pol) and (b) two zinc-finger nucleases (ZFNs) which, unlike the AcsI and ApoI homeodomains, possess specificity to >18 base-pair sequences uniquely present within the HIV-pol gene (ZifHIV-polFN). Another 15 ZFNs targeting >18 bp sequences within the complete HIV-1 proviral genome were constructed (ZifHIV-1FN). Second, a model for constructing lentiviral vectors (LVs) that deliver and transduce a diploid copy of either ZifHIV-polFN or ZifHIV-1FN chimeric genes (termed LV- 2xZifHIV-polFN and LV- 2xZifHIV-1FN, respectively) is proposed. Third, two preclinical models for controlled testing of the safety and efficacy of either of these LVs are described using active HIV-infected TZM-bl reporter cells (HeLa-derived JC53-BL cells) and latent HIV-infected cell lines. CONCLUSION: LV-2xZifHIV-polFN and LV- 2xZifHIV-1FN may offer the ex-vivo or even in-vivo experimental opportunity to halt HIV replication functionally by directly abrogating HIV-pol-gene-action or disrupting/excising over 80% of the proviral HIV DNA from latently infected cells.
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Proof-of-principle preliminary studies demonstrate that targeting the provirus is a potential strategy for curing HIV infection.
“Nevertheless, the proof-of-principle preliminary studies described above demonstrate that targeting the provirus is a potential strategy for curing HIV infection.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [52]
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Newer Gene Editing Technologies toward HIV Gene Therapy
Manjunath, N., Yi, G., Dang, Y., & Shankar, P. (2013) · Viruses · doi:10.3390/v5112748 · Cited by 77 · see citing works
- Authors
- Wayengera, M.
- Affiliations
- Makerere University (UG)
- Corresponding author
- Wayengera, Misaki
- ORCID
- Wayengera, Misaki
- Venue
- Theoretical Biology and Medical Modelling
- Published
- 2011-07-22
- Volume
- 8
- Issue
- 1
- Pages
- 26-26
- ISSN
- 1742-4682 (ISSN-L)
- PMC
- PMC3152896
- OpenAlex
- W2165386148
- Cited by
- 21
- References
- 49
- Citations by year
- 2023: 2 · 2022: 1 · 2020: 1 · 2018: 1 · 2017: 4 · 2016: 1 · 2015: 6 · 2013: 1 · 2012: 3
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Theoretical Biology and Medical Modelling (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- zinc finger nucleases, HIV pol gene, HIV cure, lentiviral vectors, HIV gene therapy, HIV-1 replication inhibition, HIV-1 reactivation
- MeSH terms
- Base Sequence, DNA, Viral, Endonucleases, Genetic Vectors, Humans, Proviruses, Substrate Specificity, Transduction, Genetic, Genetic Therapy, HIV-1, Genes, pol, Lentivirus, Zinc Fingers, Genome, Viral
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