So just how did Spirochetal disease get mistaken for HIV? biomedcentral/1471-2148/13/164 Conclusions This study provides and explores a comprehensive map of the evolutionary selective forces operating on HIV-1. Previous studies inferring natural selection in HIV did not account for selection on synonymous substitutions, which may have possibly inflated estimates of positive selection [28]. Specifically, overlapping regions of genes are often considered problematic and are removed from analyses [9]. Here we show that complex inter-related selective forces may operate on all protein coding genes within HIV-1. This analysis underscores the association between synonymously conserved regions and functional regions at the DNA or RNA levels. HIV-1 represents one of the most studied biological systems and thus provides us with the opportunity to correlate between the inferred Ks conserved stretches and known functional regions residing within coding regions. It is noteworthy that nearly all well studied regulatory regions residing within the ORFs of HIV-1 were also detected using our methodology. Nevertheless, four synonymously conserved regions were detected with no previously reported function. An important aspect of this work was the effort to experimentally elucidate the significance of the computational predictions derived from the evolutionary models. However, the mutagenesis assay performed here on one of the stretches (pol 82–90) resulted in insignificant differences between the wild type and mutated constructs. Insignificant differences between wild type and mutated clones were also obtained by Ngandu et al. [26], who experimentally tested the role for a synonymous conserved region within env. Notably, these experiments were performed in cell cultures, which do not necessarily mimic natural infections of CD4+ cells. For instance, interactions with salient host proteins (such as the interaction between Tetherin and Vpu) are often dependent on the specific cell-line used [39]. In addition, it is possible that these synonymous mutations reduce viral fitness, but this reduction is not significant enough to be revealed after only a single infection cycle. Finally, since this stretch may have an important role only in the context of the virus interaction with the host adaptive immune response, it was not discovered in the artificial cell culture experiments conducted here. Hence, future work is needed to determine the role of the novel conserved stretches detected here. Nevertheless, the methodology presented here is generic, and can be used to investigate other less-studied viral datasets to predict novel functional regions, as well as to explore the breadth of synonymous conservation in both cells and viruses. Moreover, the identification of conserved sites in viral populations should enhance PCR diagnostics of a variety of viral strains that otherwise significantly differ from each other, like in the case of HIV-1.
Posted on: Mon, 12 Aug 2013 18:21:25 +0000
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