The HIVToolbox 2 Web System Integrates Sequence, Structure, Function and Mutation Analysis

Abstract

There is enormous interest in studying HIV pathogenesis for improving the treatment of patients with HIV infection. HIV infection has become one of the best-studied systems for understanding how a virus can hijack a cell. To help facilitate discovery, we previously built HIVToolbox, a web system for visual data mining. The original HIVToolbox integrated information for HIV protein sequence, structure, functional sites, and sequence conservation. This web system has been used for almost 40,000 searches. We report improvements to HIVToolbox including new functions and workflows, data updates, and updates for ease of use. HIVToolbox2, is an improvement over HIVToolbox with new functions. HIVToolbox2 has new functionalities focused on HIV pathogenesis including drug-binding sites, drug-resistance mutations, and immune epitopes. The integrated, interactive view enables visual mining to generate hypotheses that are not readily revealed by other approaches. Most HIV proteins form multimers, and there are posttranslational modification and protein-protein interaction sites at many of these multimerization interfaces. Analysis of protease drug binding sites reveals an anatomy of drug resistance with different types of drug-resistance mutations regionally localized on the surface of protease. Some of these drug-resistance mutations have a high prevalence in specific HIV-1 M subtypes. Finally, consolidation of Tat functional sites reveals a hotspot region where there appear to be 30 interactions or posttranslational modifications. A cursory analysis with HIVToolbox2 has helped to identify several global patterns for HIV proteins. An initial analysis with this tool identifies homomultimerization of almost all HIV proteins, functional sites that overlap with multimerization sites, a global drug resistance anatomy for HIV protease, and specific distributions of some DRMs in specific HIV M subtypes. HIVToolbox2 is an open-access web application available at [http://hivtoolbox2.bio-toolkit.com].

GigaAssay – a high-throughput assay system for molecular functions and cell processes

“…Tat has 18 reported PTMs of five different types. 24,25 Mutations of most covalently modified residues at a single PTM positions did not impact transcriptional activity. We show a couple of examples that highlight the benefits of GigaAssay results in interpretation.…”

“…Most interactions of these PPI sites are in a hotspot from residues 29-60. 25,28 The most sensitive interactions are that of Cyclin T1 and Importinb. CyclinT1 makes contacts with 15 amino acids in a Tat crystal structure, mostly in the Core region; 13 positions have at least one mutant that blocks Tat transactivation, and CyclinT1 is a key protein for recruiting RNA polymerase.…”

The Infectious Disease Ontology in the age of COVID-19

“…Meningitis Ontology (IDOMEN) [38] Draft version uploaded on November 27, 2019 [39] Plant Disease Ontology (IDOPlant) [40] Draft version released in 2012 [41] Staphylococcus aureus Infectious Disease Ontology (IDOSA) [11,19,42] Released on June 22, 2012 [43] Schistosomiasis Ontology (IDOSCHISTO) [44] Most recent version uploaded on October 23, 2013 [45] HIV Ontology (IDOHIV) [46] Most recent version uploaded to BioPortal on April 4, 2017 [47] below, for our purposes here, we note that creating pathogen-type specific reference ontology extensions of IDO Core creates fewer opportunities for misalignment among extensions. Much like a researcher who seeks to represent influenza can rely on IDO Core as a reliable starting point, and so not need to reflect on what exactly, say, an "infectious disease" is, similarly the same researcher importing a virus-specific extension of IDO Core would not need to reflect on what exactly, say, a "virus" is.…”

Minimotifs dysfunction is pervasive in neurodegenerative disorders

“…At least 48 PTMs of protein have been identified in NDs, and other neurotoxic proteins with long polyQ tracts have many PTMs [218,219]. Because minimotifs are located on the surfaces of all proteins and cover almost the entire surface of many proteins [220–223], it is not surprising that perturbing minimotifs results in abnormal neurotoxic aggregation. Given their prevalence in neurotoxic aggregate formation and stability, a betting understanding of how minimotifs cooperate to induce and inhibit neurotoxic aggregates would provide a better understanding of ND etiology and open the door for new types of therapeutic intervention.…”