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closeReferee comments: Referee 3
Posted by PLOS_ONE_Group on 03 Apr 2008 at 19:15 GMT
Referee 3's review:
Using all available genomic sequences of the newly identified, so far non-cultivatable human rhinovirus types (termed "HRV-A2", "HRV-C" or "HRV-X"), of a number of HRV-As and HRV-Bs and of representative enteroviruses, the authors carried out extensive sequence and structure comparisons. They essentially reach the same conclusion put forward earlier by others and by the same group in that the new HRV types are phylogenetically distant and should be classified as a new subgenus. They compared the severity of symptoms caused by these types as well and found, also in agreement with earlier data that they appear to cause somewhat more severe disease.
Sequence alignments, analysis of phylogenetic relationship, modelling, and structure comparison were carried out with the necessary care but lack controls (i.e. comparison of a 3D structure obtained experimentally with its corresponding predicted model) and estimations of the accuracy of the models. Receptor footprints are depicted as the backbones of the capsid proteins. I am not convinced that this alone (in the absence of the side-chains) is sufficient information to judge upon receptor usage; patterns of charge and hydropathy also need to be considered.
The manuscript is overloaded with figures and tables that, to my opinion, fail to provide much more information than already published reports. Furthermore, much of the data remain speculative as long not proven experimentally. I recon that this is so far not possible because of the failure of the HRV-C types to replicate in tissue culture. Nevertheless, based on the implicit preliminary character of the findings, the manuscript might only warrant publication in a more theoretical journal.
Figure legends are missing.
Minor points:
p. l.:"In all HRV-C the last amino acid residue is an isoleucine instead of a phenylalanine". Does this mean anything?
p. 10, l. 226 and Fig. 1b: I do not see that all asterisks are at "plunges" as indicated in the text.
p. 12, l. 272: not VLDL but VLDLR is a receptor for minor group HRVs
p.15, l.346: "Firstly, we identified that HRV-QPM did not perfectly match the structure of any current receptor..." How should the virus match the receptor? Why did they not carry out comparisons as in Laine et al. 2006 and in Verdaguer et al. 2004? Key amino acid residue(s) in the minor and the major group at least indicate the possibility of receptor recognition!
p.19, l.434: "The VP1 BC and HI loops serve as the VLDL receptor (VLDL-R) for minor group HRVs [10,42,43] and the HI loop....". I suppose this should mean "the loops are being recognized by the VLDL-receptor....
It is never mentioned that minor group HRVs not only recognize VLDL-R but also LDLR and LRP.
Table 2: an evenly spaced font (such as Curier) should be used to better show the correspondingly aligned residues.
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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.