https://orcid.org/0000-0003-3785-7430
Peer Review History
| Original SubmissionAugust 18, 2020 |
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Dear Dr Vanni, Thank you very much for submitting your manuscript "The Latency-Associated Transcript Locus of Herpes Simplex Virus 1 is a Virulence Determinant in Human Skin" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations. Specifically, please pay attention to issues brought up by all three reviewers in regards to inconsistencies in the body of the results for Figure 3 versus the Figure legend. If all of the items are addressed as detailed by the reviewers, I hope to make a final decision without sending the manuscript out for a final review. Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out [2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments. Sincerely, Paul D. Ling, Ph.D. Associate Editor PLOS Pathogens Blossom Damania Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** Reviewer Comments (if any, and for reference): Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: Figures 3D-G are numbered correctly in figures and legends but incorrectly in the body of the Results. Please clarify that the significant results at 4dpi which become insignificant at 7 (?not 8) dpi are due to lack of residual keratinocytes destroyed by cytopathic spread of wt virus? Figure 3E adds little as the results are not significant for the reasons explained. Either further replicates are needed for even nonparametric statistics or the results deleted or presented as supplementary figures. The two other LATS mutants are sufficiently convincing. Reviewer #2: The revised manuscript, titled “The Latency-Associated Transcript Locus of Herpes Simplex Virus 1 is a Virulence Determinant in Human Skin”, reports that HSV-1 viruses mutated to interfere with viral transcription in the LAT locus can’t spread in human skin xenografts and cultured skin explants. The observation is interesting and potentially significant in the HSV-1 pathogenesis. The careful analysis and comprehensive comparison on wide-type and mutant viral genomes is to be praised in the detailed characterization of virus phenotypes. Prior to this study, LAT has not been implied in the lytic infection of HSV life cycle. The authors showed that deletions of the upstream of LAT promoter and 5’ LAT region, as depicted in the strain 17ΔN/H, severely impaired HSV replication and lesion formation in skin. However, this defect in virus spread was caused neither by the defect in 2kb LAT production, which is the hall mark of HSV latency, nor by many nonsynonymous mutations found in the viral coding regions. Based on detailed mapping on the transcripts produced in the LAT locus, it seems like the 0.7 kb transcript upstream of LAT promoter and/or the 5’ exon sequences in the mLAT could be responsible for the observed phenomenon. The author added KOSΔPST mutant and confirmed the defective phenotype. But the mutation in ΔPST overlaps with 0.7kb transcript, so as 17ΔN/H. Since the 0.7kb transcript has been suggested in the virulence of HSV-1 17syn+, further evaluation using mutants separating in the two regions might be needed in providing clarity on the role of LAT in HSV-1 skin pathogenesis. Reviewer #3: The authors have made significant improvements to this paper, which now provides compelling evidence that the HSV-1 latency associated transcripts act as a virulence determinant in human skin. The inclusion of additional LAT mutant viruses and, where available, revertant viruses strengthens their message. The inclusion of full sequence data for the mutant viruses will also act as a wake-up call to research groups working in this complex field. This is an important body of work that adds important new information concerning the role of LATs in pathogenesis outside of known functions in neuronal cells. The authors should carefully review Figure 3, and the text describing this Figure in the results - it appears that some panels are miss-labelled/missing. ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: (No Response) Reviewer #2: (No Response) Reviewer #3: (No Response) ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: (No Response) Reviewer #2: There is mixed use of LATs with LAT locus in the Author Summary, starting on line 44. Since the LAT splicing mutant have no effect in skin virulence, plus it is unknown whether other transcripts in the LAT promoter region express in the latency, it is more precise to use LAT locus than LATs, to avoid misleading. Fig. 3C, Fig. 3D, 3E, 3F, 3G, seem shifted, the text and figure don’t match. There is one panel missing in Fig. 3. Line 357-359 needs modification. Fig. 1 and 2C didn’t verify ICP0 retained its ubiquitin ligase function. Fig.2C only showed ICP0 expression. Line 411-412 needs modification. Three references (47, 49, 50) only used 17 and KOS strain in cell culture. No mention on F strain. Reviewer #3: The authors should carefully review Figure 3, and the text describing this Figure in the results - it appears that some panels are miss-labelled/missing. ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: No Figure Files: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Data Requirements: Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5. Reproducibility: To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plospathogens/s/submission-guidelines#loc-materials-and-methods |
| Revision 1 |
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Dear Dr Vanni, We are pleased to inform you that your manuscript 'The Latency-Associated Transcript Locus of Herpes Simplex Virus 1 is a Virulence Determinant in Human Skin' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Paul D. Ling, Ph.D. Associate Editor PLOS Pathogens Blossom Damania Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************************************************** Reviewer Comments (if any, and for reference): |
| Formally Accepted |
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Dear Dr Vanni, We are delighted to inform you that your manuscript, "The Latency-Associated Transcript Locus of Herpes Simplex Virus 1 is a Virulence Determinant in Human Skin," has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens |
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