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Thanks for attending to the previous concerns.
[# PeerJ Staff Note - this decision was reviewed and approved by Vladimir Uversky, a PeerJ Section Editor covering this Section #]
Please attend promptly to the comment form reviewer 1.
In addition, PeerJ staff suggest that the title should be edited to include the indefinite article:
> Genetic polymorphisms in the C19orf66 gene influenced HIV-1 infection in a Yunnan population
The authors have responded to my concerns and questions in the appropriate manner. I expect that this study will help to elucidate the in vivo role of C19orf66 in humans. One point I would like to request in minor revision is that the predicted effect of the SNPs on the transcription of C19orf66 mRNA should be mentioned in this manuscript as the HBV study has been published in Front Cell Infect Microbiol.
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I consider that the authors have adequately addressed my comments.
The authors made additional analyses that support the findings.
The author have improved the discussion and conclusion of the manuscript.
No comment.
The manuscript presents interesting findings; however, it can be improved to better interpret the results and an adequate discussion of the findings. The conclusion could be reconsidered in terms of the findings.
Please attend to the reviewers' comments.
[# PeerJ Staff Note: Please ensure that all review and editorial comments are addressed in a response letter and any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate. #]
[# PeerJ Staff Note: The review process has identified that the English language must be improved. PeerJ can provide language editing services - please contact us at copyediting@peerj.com for pricing (be sure to provide your manuscript number and title) #]
In this manuscript, Zhang et al. report the investigation of genetic polymorphisms in the C19orf66 (SHFL) gene in HIV-1 infected individuals. C19orf66/SHFL is one of the interferon-stimulated genes that has been shown to inhibit a variety of RNA and DNA viruses, including HIV-1. This study focused on three SNPs and claimed that the C and T allele frequencies of rs12611087 in the C19orf66 gene were statistically different compared to HIV-infected individuals. However, the differences were quite small and an insufficient number of infected and healthy individuals were studied. In addition, another major problem of this study is that no functional association between the CC or CT genotype of rs12611087 and the molecular characteristics of C19orf66 (i.e., effect on the expression and/or antiviral activity of C19orf66) is shown. Therefore, the association of C19orf66 genetic polymorphisms with the risk of HIV-1 infection is far from convincing. Although the impact of SNPs in the human genome on the antiviral activity of C19orf66 is an interesting topic, this study does not prove it at all and is superficial.
It is unclear why the authors focused on only three SNPs (rs77076061, rs1979262, and rs12611087).
There is no thoughtful discussion of why infection of the subtype CRF 08_BC, not other subtypes, was affected by the CC genotype of rs12611087.
It should also be noted that the references do not adequately cover the relevant literature.
There are many typos in the manuscript that should be corrected. Some examples are:
- Last part of the Abstract, could be influenced instead of could be influence.
- Line 48, participant instead of participate
- Line 50, probably a grammar connector is missing.
- Line 101, GraphPad instead of GraohPad
- Line 109-110, the monocytes count was also similar between groups.
- Line 122, the genotype AA is repeated. The first one mentioned is about TT genotype.
- All tables must include the definition of each abbreviation mentioned in the table, as a part of the footnote.
- Table 3, please include the n of each genotype group.
- Title of Table 4, probably it should be specified at the end of the title: different viral genotype or subtype. It sound redundant with the SNPs genotypes.
- The first two paragraphs of the Discussion are more about the rationale of the study, and authors could deep in other issues.
- The supplemental material contains information in other language different to English.
- Did authors assessed for Hardy-Weinberg equilibrium? It might be important to report the analysis, at least for the control group.
- For the genetic association study (Table 2), the analyses of genetic models (dominant, recessive, etc.) could enrich the report.
- Did authors evaluate the statistical power of the found associations? How can this limitate the findings?
- I consider that the biochemical parameters could be better explained. Is the difference found between subjects with HIV and controls clinically relevant? The differences observed in the biochemical indexes are out of range? this difference could indicate severity or worst prognosis? I think authors could add this to discussion Section.
- Authors mentioned a genotype and an allele as protective factors, but is difficult to stablish that it was a protective condition if controls were not exposed to HIV and avoid the infection. This could be discussed or at least clarified in the text. Moreover, the CC genotype found as a "protective factor" was then associated with the probability of infection with a particular viral subtype (lines 133-135). Authors should better discussed the genetic association finding.
- Table 4, it is not clear which was the comparison group in each case. Please specify.
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I consider that the manuscript present interesting findings, however it can be improved in order to get a better interpretation of the results and an adequate discussion of the findings.
The conclusion could be reconsidered in terms of the findings. What do authors are considering in lines 186 and 187? The usage of the gene as a drug target, as a pharmacogenetic biomarker? In the present study authors did not assess outcome or treatment response, so probably a direct impact in the treatment could still be far away.
This interesting article is tersely written but understandable. It summarises the current status of the C19orf66 and HIV research areas nicely and is well balanced. The only issue I encountered was that one of the reported SNPs (rs77076061) is not recognised in any database and thus could not be checked. This should be investigated in case the wrong number has been reported.
The experimental approach is solid and the methods are clear. It would be useful to have information about the anti-retroviral drug regime and status of the HIV+ individuals.
The association between C19orf66 (SHFL) SNPs and immune status is potentially a very interesting finding. It would be useful if the authors could suggest some possible implications of their findings in terms of C19orf66 gene expression. I note that the SNPs rs1979262 and rs12611087 map to introns not coding sequences. Are these SNPs predicted to have an effect on gene expression through modulation of splicing?
In the SI files, the word female is spelled incorrectly throughout (femaleale).
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