Targeted gene disruption to cure HIV
Open accessAbstract
PURPOSE OF REVIEW: Recent clinical research suggests that an HIV-infected patient with lymphoma who was transplanted with bone marrow homozygous for a disrupted mutant CCR5 allele has no remaining HIV replication and is effectively cured of HIV. Here, we discuss the approaches of disrupting host and viral genes involved in HIV replication and pathogenesis with the aim of curing patients with HIV. RECENT FINDINGS: Data from the 'Berlin patient' suggest that targeted gene disruption can lead to an HIV cure. This review discusses the recent advances in the field of gene disruption toward the development of an anti-HIV therapy. We will introduce the strategies to disrupt host and viral genes using precise disruptions, imprecise disruptions, or site-specific recombination. Furthermore, the production of engineered rare-cutting endonucleases (zinc finger nucleases, TAL effector nucleases, and homing endonucleases) and recombinases that can recognize specific DNA target sequences and facilitate gene disruption will be discussed. SUMMARY: The discovery of a gene disruption approach that would cure or efficiently confine HIV infection could have broad implications for the treatment of millions of people infected with HIV. An efficient 'one-shot' curative therapy not only would give infected patients hope of a drug-free or treatment-free future, but also could reduce the huge financial burden faced by many countries because of widespread administration of highly active antiretroviral therapy.
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Nuclease-based approaches have been used to disrupt HIV-1 entry coreceptors CCR5 or CXCR4 and proviral DNA-encoding viral proteins.
“These approaches have been used to disrupt HIV-1 entry coreceptors C-C chemokine receptor 5 (CCR5) or C-C-C chemokine receptor 4 (CXCR4) and proviral DNA-encoding viral proteins”
From RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection (2014) · cites this paper as [8]
Engineered nucleases including ZFN, TALEN, and CRISPR Cas9 can disrupt target genes and have raised prospects of selectively deleting HIV-1 proviral DNA integrated into the host genome.
“Advances in the engineered nucleases including zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR) associated 9 (Cas9) that can disrupt target genes have raised prospects of selectively deleting HIV-1 proviral DNA integrated into the host genome”
From RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection (2014) · cites this paper as [8]
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RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection
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“With respect to the use of this technology in the setting of HIV infection, several lines of research have been proposed including (i) disrupting HIV-1 entry coreceptors (CCR5, CXCR4) and proviral DNA-encoding viral proteins [13,22]; CCR5 gene targeting ZFNs are in phase II clinical trials for HIV/AIDS treatment [23],…”
MethodCRISPR/Cas9: a tool to eradicate HIV-1
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BackgroundSchiffer, J. T., Swan, D. A., Stone, D., & Jerome, K. R. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003131 · Cited by 44 · see citing works
“In contrast, our approach here is to use DNA cleavage enzymes that directly target latent viral genomes, rather than host cell viral entry receptors, to be delivered to infected cells as transgenes within viral vectors [10,17].”
MethodThe Impact of HIV-1 Genetic Diversity on CRISPR-Cas9 Antiviral Activity and Viral Escape
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Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy
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“We and others have suggested that targeted endonucleases might represent a definitive curative approach to many chronic infections with DNA viruses, including HSV, Hepatitis B virus, HIV, human papillomavirus, and others (11, 28, 30).”
BackgroundSelf-citationDamaging the Integrated HIV Proviral DNA with TALENs
Strong, C. L., Guerra, H. P., Mathew, K. R., Roy, N., Simpson, L. R., & Schiller, M. R. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125652 · Cited by 37 · see citing works
“The use of TALENs for treating HIV latency has been recently suggested [29,30].”
BackgroundEradication of HIV and Cure of AIDS, Now and How?
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HIV-1 Latency and Eradication: Past, Present and Future
Datta, P. K., Kaminski, R., Hu, W., Pirrone, V., Sullivan, N. T., Nonnemacher, M. R., Dampier, W., Wigdahl, B. L., & Khalili, K. (2016) · Current HIV Research · doi:10.2174/1570162x14666160324125536 · Cited by 34 · see citing works
Viral diversity is an obligate consideration in CRISPR/Cas9 designs for targeting the HIV reservoir
Roychoudhury, P., Feelixge, H. S. D. S., Reeves, D. B., Mayer, B. T., Stone, D., Schiffer, J. T., & Jerome, K. R. (2018) · BMC Biology · doi:10.1186/s12915-018-0544-1 · Cited by 32 · see citing works
Self-citationWeber, N. D., Aubert, M., Dang, C. H., Stone, D., & Jerome, K. R. (2014) · Virology · doi:10.1016/j.virol.2013.12.037 · Cited by 28 · see citing works
Self-citationDigital detection of endonuclease mediated gene disruption in the HIV provirus
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CRISPR/Cas9 and Genome Editing for Viral Disease—Is Resistance Futile?
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HIV cure strategies: which ones are appropriate for Africa?
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“This results in deletions or additions at the selected gene target site [22, 129].”
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“disruption and bone marrow transplantation [39,40], do not address the major impact of neuroAIDS.”
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“The identification of specific CD4þ T-cell subpopulations that serve as preferred sites for viral persistence of X4-tropic virus may be relevant in the context of current strategies aiming at inducing a functional cure of HIV-1 through therapeutic manipulation of CCR5 surface expression [17], and in the setting of tre…”
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“Gene disruption and bone marrow transplantation are recent investigational cures for HIV [19, 20].”
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“Efficient gene-modification activity has been achieved by a number of systems including clustered regularly interspaced short palindromic repeats (CRISPR)associated protein 9 (CRISPR/Cas9) technologies [24], the transcription-activator-like effector nucleases (TALENs), zinc finger nucleases [25,26], and homing endonuc…”
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“Gene disruption and bone marrow transplantation are investigated for their potential to cure HIV (32, 33), but these are risky and expensive procedures that are currently not feasible for the treatment of large numbers of patients.”
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“In addition to targeting the HIV-1 genome, an alternative approach is to employ CRISPR/Cas9 to target cellular genes that encode proteins that are required for HIV-1 infection such as C-C chemokine receptor type (CCR) 5, which is a coreceptor for HIV-1 entry [47, 48].”
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Background
- Authors
- Stone, D., Kiem, H.-P., & Jerome, K. R.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Jerome, Keith R.
- Venue
- Current Opinion in HIV and AIDS
- Published
- 2013-05
- Volume
- 8
- Issue
- 3
- Pages
- 217-223
- ISSN
- 1746-630X (ISSN-L)
- PMC
- PMC4226633
- OpenAlex
- W1996175658
- Cited by
- 55
- References
- 56
- Citations by year
- 2025: 3 · 2024: 1 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 8 · 2013: 5
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in HIV and AIDS (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (RL1HL092554, RL HL92554)
- National Institute of Allergy and Infectious Diseases (U19AI096111, R01 AI80326, R01AI080326, P30AI027757)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- HIV cure, targeted gene disruption, CCR5, Berlin patient, bone marrow transplantation, HIV replication, site-specific recombination, zinc finger nucleases, TALEN, homing endonucleases
- MeSH terms
- Endonucleases, Humans, HIV Infections, Gene Targeting
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