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A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support.

ABSTRACT: CCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4-capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the determinants of HIV-2 coreceptor usage. Therefore, we developed a data-driven web service for the prediction of HIV-2 coreceptor usage from the V3 loop of the HIV-2 glycoprotein and used the tool to identify novel discriminatory features of X4-capable variants.Using 10 runs of tenfold cross validation, we selected a linear support vector machine (SVM) as the model for geno2pheno[coreceptor-hiv2], because it outperformed the other SVMs with an area under the ROC curve (AUC) of 0.95. We found that SVMs were highly accurate in identifying HIV-2 coreceptor usage, attaining sensitivities of 73.5% and specificities of 96% during tenfold nested cross validation. The predictive performance of SVMs was not significantly different (p value 0.37) from an existing rules-based approach. Moreover, geno2pheno[coreceptor-hiv2] achieved a predictive accuracy of 100% and outperformed the existing approach on an independent data set containing nine new isolates with corresponding phenotypic measurements of coreceptor usage. geno2pheno[coreceptor-hiv2] could not only reproduce the established markers of CXCR4-usage, but also revealed novel markers: the substitutions 27K, 15G, and 8S were significantly predictive of CXCR4 usage. Furthermore, SVMs trained on the amino-acid sequences of the V1 and V2 loops were also quite accurate in predicting coreceptor usage (AUCs of 0.84 and 0.65, respectively).In this study, we developed geno2pheno[coreceptor-hiv2], the first online tool for the prediction of HIV-2 coreceptor usage from the V3 loop. Using our method, we identified novel amino-acid markers of X4-capable variants in the V3 loop and found that HIV-2 coreceptor usage is also influenced by the V1/V2 region. The tool can aid clinicians in deciding whether coreceptor antagonists such as maraviroc are a treatment option and enables epidemiological studies investigating HIV-2 coreceptor usage. geno2pheno[coreceptor-hiv2] is freely available at http://coreceptor-hiv2.geno2pheno.org .

SUBMITTER: Doring M

PROVIDER: S-EPMC5168878 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support.

Döring Matthias M Borrego Pedro P Büch Joachim J Martins Andreia A Friedrich Georg G Camacho Ricardo Jorge RJ Eberle Josef J Kaiser Rolf R Lengauer Thomas T Taveira Nuno N Pfeifer Nico N

Retrovirology 20161220 1

<h4>Background</h4>CCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4-capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the det ...[more]

PMID: 27998283

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Project description:Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.

Project description:BackgroundClinical scores are frequently used in the diagnosis and management of stroke. While medical calculators are increasingly important support tools for clinical decisions, the uptake and use of common medical calculators for stroke remain poorly characterized.ObjectiveWe aimed to describe use patterns in frequently used stroke-related medical calculators for clinical decisions from a web-based support system.MethodsWe conducted a retrospective study of calculators from MDCalc, a web-based and mobile app-based medical calculator platform based in the United States. We analyzed metadata tags from MDCalc's calculator use data to identify all calculators related to stroke. Using relative page views as a measure of calculator use, we determined the 5 most frequently used stroke-related calculators between January 2016 and December 2018. For all 5 calculators, we determined cumulative and quarterly use, mode of access (eg, app or web browser), and both US and international distributions of use. We compared cumulative use in the 2016-2018 period with use from January 2011 to December 2015.ResultsOver the study period, we identified 454 MDCalc calculators, of which 48 (10.6%) were related to stroke. Of these, the 5 most frequently used calculators were the CHA2DS2-VASc score for atrial fibrillation stroke risk calculator (5.5% of total and 32% of stroke-related page views), the Mean Arterial Pressure calculator (2.4% of total and 14.0% of stroke-related page views), the HAS-BLED score for major bleeding risk (1.9% of total and 11.4% of stroke-related page views), the National Institutes of Health Stroke Scale (NIHSS) score calculator (1.7% of total and 10.1% of stroke-related page views), and the CHADS2 score for atrial fibrillation stroke risk calculator (1.4% of total and 8.1% of stroke-related page views). Web browser was the most common mode of access, accounting for 82.7%-91.2% of individual stroke calculator page views. Access originated most frequently from the most populated regions within the United States. Internationally, use originated mostly from English-language countries. The NIHSS score calculator demonstrated the greatest increase in page views (238.1% increase) between the first and last quarters of the study period.ConclusionsThe most frequently used stroke calculators were the CHA2DS2-VASc, Mean Arterial Pressure, HAS-BLED, NIHSS, and CHADS2. These were mainly accessed by web browser, from English-speaking countries, and from highly populated areas. Further studies should investigate barriers to stroke calculator adoption and the effect of calculator use on the application of best practices in cerebrovascular disease.

Dataset Information

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support.

Publications

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support.

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