Dear Mr. Kreger,

Thank you very much for submitting your manuscript "A hybrid stochastic-deterministic approach to explore multiple infection and evolution in HIV" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

There are important comments from the referees on the novelty of the methodology, on the biological assumptions, and on the emphasis on the methodology vs. biological results. There are also concerns about the structure and clarity of the manuscript.  A more clear exposition of both, and a further emphasis on the contributions on HIV, seem to be required. 

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the 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.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. 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,

Mercedes Pascual

Associate Editor

PLOS Computational Biology

Nina Fefferman

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: This paper describes a hybrid stochastic/deterministic approach applied to HIV. The underlying model studied takes into account synaptic cell-to-cell transmission (for multiple strain infections), and neutral, and advantageous/disadvantageous mutations. ODE models are widely adopted to study viral dynamics, despite their downsides when it comes to rare mutational events. The approach described herein therefore has the potential for impact, given that it addresses such events during acute infection, as described in this paper.

1) This paper would benefit significantly from reorganization. If the emphasis is on the computational method, then parts of the SI should be moved to the main paper. I believe this would help the reader better grasp the approach. I would suggest at a minimum that the first section of the SI (full description of the mathematical model) be moved into the main paper, to give more context to the later sections. As written, the main takeaways and the focus of the paper aren't clearly distinguishable.

2) The authors should touch upon why cells non-dimensionalized in the model. Would this be necessary for all implementations of the hybrid approach? Later in figure legends, cells are expressed in cells. If cell units are not not non-dimensionalized, than the units in Table 1 aren't correct.

3) A more detailed discussion on other hybrid approaches should be undertaken in the introduction. These include, but aren't limited to, tau-leaping and fast-slow systems.

4) Why is free virus not explicitly included in the model (Eqs. 1-5)? As written, the rate of free virus infection is proportional to beta and interactions between uninfected and all infected cells, why not include an equation for virions?

5) Figure 1 and similar figures: the dots are quite large and the inner panel is doubling up information. Since multiple runs of the stochastic algorithm are needed, it would be better to always include mean + SD (or some other metric of dispersion). I would suggest remaking these large dots with another smaller marker and tails.

6) Figure 2: What do the royal blue and bright red single lines represent?

Reviewer #2: Please see the attache pdf file of the review report.

Reviewer #3: Please see attached pdf.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: None

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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 in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: ReviewReport_Kreger.pdf

Attachment

Submitted filename: Kreger_et_al.pdf

Dear Mr. Kreger,

Thank you very much for submitting your manuscript "A hybrid stochastic-deterministic approach to explore multiple infection and evolution in HIV" for consideration at PLOS Computational Biology. Your manuscript was reviewed by members of the editorial board and by the same independent reviewers who commented on your original submission. The reviewers indicated that their concerns have now been largely addressed.  On this basis, we are  ready to accept this manuscript for publication once you consider and clarify two pending issues they have raised, on  the description of the algorithm and Piecewise Deterministic Markov Processes and on the units on the table.  It would be worthwhile to acknowledge the literature on efficient algorithms for PDMP and to discuss your algorithm in that context 

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 your responses to the above two comments, and a brief 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,

Mercedes Pascual

Associate Editor

PLOS Computational Biology

Nina Fefferman

Deputy Editor

PLOS Computational Biology

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A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have made great improvements to the flow in their revisions, and have responded to my previous questions. I am not sure why the variables with * in Table 1 do not simply have units in the units column instead of the note in the caption, but I assume the authors have a specific reason for this choice.

Reviewer #2: Authors have addressed all my comments. I thank them for the updated work. I do not have any further comments and recommend for publication in PLOS Computational Biology.

Reviewer #3: Please see the comment in the attached PDF.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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 in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References:

Review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Attachments

Attachment

Submitted filename: Kreger_et_al_v2.pdf

Dear Mr. Kreger,

We are pleased to inform you that your manuscript 'A hybrid stochastic-deterministic approach to explore multiple infection and evolution in HIV' has been provisionally accepted for publication in PLOS Computational Biology.

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 Computational Biology. 

Best regards,

Mercedes Pascual

Associate Editor

PLOS Computational Biology

Nina Fefferman

Deputy Editor

PLOS Computational Biology

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