The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index; none of the 29 sources its claims cite is checked for support yet.
RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection
Open accessAbstract
Significance: Latent viral infection is a major obstacle for effective antiviral treatment and presents a continuous risk to the host. The dormant viral genome during latent infection provides few therapeutic targets other than itself for antiviral drug development. This study demonstrates the clearance of latent Epstein–Barr virus genomes in a subpopulation of Burkitt’s lymphoma patient-derived cells with clustered regularly interspaced short palindromic repeat/Cas9 nuclease. Viral genome destruction leads to proliferation arrest and apoptosis in Epstein–Barr virus-infected cells, with no observed cytotoxicity to noninfected cells. Although many hurdles remain before this approach could be used in the clinic, this strategy may lead to a generalized approach to cure latent viral infections.
Overview
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Written from the paper’s full text.
TL;DR
The paper shows that CRISPR/Cas9 can be targeted to the latent Epstein-Barr virus genome in Burkitt’s lymphoma cells, causing large viral deletions, proliferation arrest, apoptosis, and complete EBV clearance in a subpopulation of cells. It proposes RNA-guided endonuclease therapy as a potential strategy to cure latent herpesviridae infection, while noting that delivery and clinical development remain unresolved.
Key findings
- In Raji cells, adding the EBV origin of replication (*oriP*) to the CRISPR plasmid increased transfection efficiency from <10% at 48 h to >60%.
- Untreated Raji cells averaged 42 EBV genome copies per cell; treatment with the guide RNA mixture sgEBV1–7 reduced EBV load by ∼65% in live cells and ∼85% in dead cells. Single-cell analysis found that among 71 quality-controlled treated cells, 19 had no detectable EBV, 30 had dramatically decreased EBV load, and 22 were unchanged; the paper states that around 25% of treated cells were completely cleared of EBV and another 50% showed substantial decrease.
- Guide RNAs targeting structural repeat regions (sgEBV1/2/6) completely stopped cell proliferation despite only a 26% decrease in EBV load, whereas sgEBV4/5 reduced the EBV genome by 85% but did not suppress proliferation as effectively as the full mixture.
- Treatment caused apoptosis markers and no measurable proliferation change in EBV-negative DG-75 Burkitt’s lymphoma cells or primary human IMR90 lung fibroblasts, suggesting negligible cytotoxicity.
Methods
- Burkitt’s lymphoma cell lines Raji, Namalwa, and DG-75, plus primary human lung fibroblast IMR-90, were cultured under standard conditions; CRISPR/Cas9 plasmids were modified from pX458 to include the pmax promoter, sgRNA, and EBV *oriP*, and delivered by nucleofection.
- Seven guide RNAs were designed against the EBV B95-8 reference genome, targeting structural repeat regions, EBNA1, and EBNA3C/LMP1; editing was assessed by SURVEYOR assays, PCR, and Sanger sequencing.
- Viral load was quantified by digital PCR on the Fluidigm BioMark system and by single-cell whole-genome amplification on the Fluidigm C1 system, with flow sorting and qPCR for EBV and human somatic loci.
Limitations
- The paper states that further development into a practical therapeutic will require more sophisticated delivery approaches, which were beyond the scope of the study; it also states that off-target cleavage is a major concern for nuclease therapy, though it cites prior work suggesting off-target effects are not a substantial impediment for nonhuman genome targets.
- The paper states that a single treatment did not eliminate all virus-infected cells, but argues that multiple doses could amplify efficacy geometrically and that partial elimination might allow immune control of residual latent infection.
- Evident from the text: the work is limited to cultured cell lines and does not demonstrate in vivo delivery, animal-model efficacy, or direct off-target/safety assessment in this study; guide RNA delivery and plasmid replication are described as stochastic.
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Claims the paper makes
25 Own result · 11 Own interpretation · 10 Not checked yet · 3 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patient-derived cells from a Burkitt's lymphoma with latent Epstein-Barr virus infection showed dramatic proliferation arrest and a concomitant decrease in viral load after exposure to a CRISPR/Cas9 vector targeted to the viral genome.”
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In the paper
“After 5 or 7 d of sgEBV2 transfection, we obtained ∼0.4-kb bands from the same PCR amplification (Fig. 2B).The ∼1.4-kb deletion is the expected product of repair ligation between cuts in the first and the last repeat unit (Fig. 2A).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
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In the paper
“Flow-cytometry scattering signals clearly revealed alterations in the cell morphology after sgEBV1-7 treatment, as the majority of the cells shrank in size with increasing granulation (Fig. 3 B-D) (population P4 to P3 shift).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
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In the paper
“Annexin V staining revealed a distinct subpopulation of cells with intact cell membrane but exposed phosphatidylserine, suggesting cell death through apoptosis (Fig. 3 E-G).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
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In the paper
“Cells treated with a Cas9-plasmid with oriP but no sgEBV had an EBV load that was reduced by ∼50%.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
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In the paper
“Cells treated with a Cas9 plasmid that lacked oriP or sgEBV did not have an obvious difference in EBV load difference from the untreated control.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
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In the paper
“Despite efficient DNA cleavage, we were surprised to see that the subsequently repaired EBV genomes could still drive host-cell proliferation.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On average, each untreated Raji cell has 42 copies of EBV genome (Fig. 4A).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells in population P3 also demonstrated compromised membrane permeability by DAPI staining (Fig. 3 E-G).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
boosted- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SURVEYOR assays confirmed efficient editing of individual sites (Fig. S1).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 23
- The quote only partly states this claim. 1
- Probably not a substantial claim. 7
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In the paper
“As expected, cells treated with Cas9 plasmids that lacked oriP or sgEBV lost EGFP expression within a few days and proliferated with a rate similar rate to the untreated control group (Fig. 3A).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Transfection of a guide RNA mixture completely suppressed virally induced cell proliferation and restored the apoptosis pathway in the cells.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although sgEBV4/5 reduced the EBV genome by 85%, they could not suppress cell proliferation as effectively as the full mixture (Fig. 3A).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Around 25% of the treated cells were completely cleared of EBV with no detectable viral DNA, and another 50% of cells showed substantial EBV load decrease relative to the untreated sample.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The addition of the guide RNA mixture sgEBV1-7 to the transfection further reduced the EBV load.The live and dead cells have ∼65% EBV and 85% decreases, respectively, compared with the untreated control, and as previously discussed these cells did not proliferate.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For the sgEBV1-7 treated sample, 71 single-cell products passed the quality control and the EBV load distribution was dramatically wider (Fig. 4E).Although 22 cells had the same EBV load as the untreated cells, 19 cells had no detectable EBV and the remaining 30 cells displayed dramatic EBV load decrease from the untreated sample.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We further demonstrated that it is possible to delete regions between unique targets (Fig. 2C).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Eight and 9 d after transfection, the cell proliferation rates did not change from the untreated control groups, suggesting negligible cytotoxicity.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
hedgedn = 2- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Guide RNAs targeting the structural sequences (sgEBV1/2/6) could stop cell proliferation completely, despite not eliminating the full EBV load (26% decrease).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment with the mixed mixture sgEBV1-7 resulted in no measurable cell proliferation and the total cell count either remained constant or decreased (Fig. 3A).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sixty-nine untreated single-cell products passed the quality control and displayed a log-normal distribution of EBV load (Fig. 4D), with almost every cell displaying significant amounts of EBV genomic DNA.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
plainn = 69- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bright-field microscopy showed obvious apoptotic cell morphology (Fig. 3 H and I) and fluorescent staining demonstrated drastic DNA fragmentation (Fig. 3 J-M).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Plasmids with Cas9-oriP and a scrambled guide RNA maintained EGFP expression after 8 d, but did not reduce the cell proliferation rate.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“DNA sequence recognition requires only a single 20-nt guide RNA and a protospacer adjacent motif, which enables one to rapidly engineer and test a large number of DNA cleavage sites (17)(18)(19)(20).”
What the sources say
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In the paper
“It has been recognized that it would be useful to target latent infections with viral genome-specific nucleases (3-5), but the challenges of engineering sequence-specific nucleases have hampered progress.”
What the sources say
- Not checked yetcites [3]
- Not checked yetcites [4] source
- Not checked yetcites [5]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 is a naturally occurring bacterial immune system that uses a novel nuclease system to protect bacteria from phage infection (6-9), and it has recently been harnessed for a variety of genome-engineering applications (10)(11)(12)(13)(14)(15)(16)(17).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The Raji cell line was the first established long-term culture from Burkitt's lymphoma patients (22,23), and is one of the most extensively studied EBV models.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Results
What the sources say
- Not checked yetcites [22]
- Not checked yetcites [23]
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although we provided seven guide RNAs at the same molar ratio, the plasmid transfection and replication process is likely quite stochastic.Some cells will inevitably receive different subsets or mixtures of the guide RNA mixture, which might affect the treatment efficiency.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Prior studies of the efficacy of endonuclease treatment of herpesviridae infections, however, had significant limitations.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
What the sources say
- Not checked yetcites [28]
- Not checked yetcites [5]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“For quality-control purposes, we performed four-loci human somatic DNA quantitative PCR on each single-cell amplification product (27) and required positive amplification from at least one locus.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Complete Clearance of EBV in a Subpopulation.
What the sources say
- Not checked yetcites [27]
plainn = 69- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Suppressing EBV activity may therefore restore the apoptosis process, which could explain the cell death observed in our experiment.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Previous studies have attributed the tumorigenic ability of EBV to its interruption of host-cell apoptosis (26).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > EBV Genome Editing.
What the sources say
- Not checked yetcites [26]
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because any practical therapeutic could be administered in multiple doses, it is not necessary to obtain complete elimination of all virus-infected cells with a single treatment; the geometric reduction effect from multiple doses will amplify the efficacy of any such treatment.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Together with recent improvements on CRISPR target specificity with dual-guide RNA designs (33)(34)(35), these studies show that off-target effects are not a substantial impediment to human genome-engineering applications and certainly do not appear to be an obstacle for applications that target nonhuman genomes (36).”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
What the sources say
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The continuous Burkitt's lymphoma cell lines derived from different patients provide a convenient and naturally occurring renewable source of material for EBV studies, which is in contrast to the lack of easily available HSV models.”
§ RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection > Discussion
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
- Rests on an assumption: The lack of an adequate in vitro model for HSV infection has hampered antiviral research.
The paper relies on this without support.
Existing antiviral therapies cannot effectively eradicate latent infection, so a cure is lacking for many prevalent viral diseases.
“Although standard antiviral therapies can suppress active viral replication, no existing treatment can effectively eradicate latent infection and therefore a cure is lacking for many prevalent viral diseases.”
The paper relies on this without support.
The dormant viral genome during latent infection provides few therapeutic targets other than itself for antiviral drug development.
“The dormant viral genome during latent infection provides few therapeutic targets other than itself for antiviral drug development.”
The paper relies on this without support.
EBNA1 is crucial for many EBV functions, including gene regulation and latent genome replication.
“EBNA1 is crucial for many EBV functions, including gene regulation and latent genome replication.”
The paper relies on this without support.
EBNA3C and latent membrane protein-1 are essential for host cell transformation.
“EBNA3C and latent membrane protein-1 are essential for host cell transformation, and we designed guide RNAs sgEBV3 and sgEBV7 to target the 5′ exons of these two proteins, respectively.”
The paper relies on this without support.
The EBV genome encodes about 85 genes, several of which are essential for lytic or latent infection.
“The EBV genome encodes about 85 genes, several of which are essential for lytic or latent infection.”
The paper relies on this without support.
EBNA1 binds to the EBV origin of replication (oriP) to maintain viral episomes and also regulates expression of other viral genes.
“EBNA1 binds to the EBV origin of replication (oriP) to maintain viral episomes; it also regulates expression of other viral genes.”
The paper relies on this without support.
The lack of an adequate in vitro model for HSV infection has hampered antiviral research.
“Thus far, the lack of an adequate in vitro model for HSV infection has hampered antiviral research.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Similarly, in a Burkitt's lymphoma cell line with latent EBV infection, CRISPR-Cas9 treatment inhibited cell proliferation and reduced viral load.42”
From CRISPR-Cas9: a new and promising player in gene therapy (2015) · cites this paper as [42]
Citations
Cites
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
RNA-Guided Human Genome Engineering via Cas9
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Metadata
- Authors
- Wang, J., & Quake, S. R.
- Affiliations
- Department of Bioengineering,
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-08-25
- Volume
- 111
- Issue
- 36
- Pages
- 13157-13162
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4246930
- OpenAlex
- W2084747588
- Cited by
- 220
- References
- 37
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 7 · 2023: 9 · 2022: 18 · 2021: 27 · 2020: 15 · 2019: 24 · 2018: 27 · 2017: 22 · 2016: 28 · 2015: 22 · 2014: 3
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (U01HL099995, U01HL099999)
- National Cancer Institute (P01CA139490, U54CA151459)
- Topics
- 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
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- CRISPR/Cas9, RNA-guided endonuclease, viral latency, herpesvirus, Epstein-Barr virus, Burkitt lymphoma, antiviral gene therapy, viral load reduction
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Base Sequence, Endonucleases, Herpesvirus 4, Human, Humans, Models, Biological, Molecular Sequence Data, Genome, Viral, Sequence Deletion, RNA Editing, Epstein-Barr Virus Infections, Cell Line, Tumor, Cell Proliferation, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems
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