title: Highly Accurate Structure-Based Prediction of HIV-1 Coreceptor Usage Suggests Intermolecular Interactions Driving Tropism.
abstract: HIV-1 entry into host cells is mediated by interactions between the V3-loop of viral glycoprotein gp120 and chemokine receptor CCR5 or CXCR4, collectively known as HIV-1 coreceptors. Accurate genotypic prediction of coreceptor usage is of significant clinical interest and determination of the factors driving tropism has been the focus of extensive study. We have developed a method based on nonlinear support vector machines to elucidate the interacting residue pairs driving coreceptor usage and provide highly accurate coreceptor usage predictions. Our models utilize centroid-centroid interaction energies from computationally derived structures of the V3-loop:coreceptor complexes as primary features, while additional features based on established rules regarding V3-loop sequences are also investigated. We tested our method on 2455 V3-loop sequences of various lengths and subtypes, and produce a median area under the receiver operator curve of 0.977 based on 500 runs of 10-fold cross validation. Our study is the first to elucidate a small set of specific interacting residue pairs between the V3-loop and coreceptors capable of predicting coreceptor usage with high accuracy across major HIV-1 subtypes. The developed method has been implemented as a web tool named CRUSH, CoReceptor USage prediction for HIV-1, which is available at http://ares.tamu.edu/CRUSH/.
authors: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, United States of America.|Texas A&M Energy Institute, Texas A&M University, College Station, TX, United States of America.
authors: Chris A
authors: CA
authors: Kieslich
authors: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, United States of America.|Texas A&M Energy Institute, Texas A&M University, College Station, TX, United States of America.
authors: Phanourios
authors: P
authors: Tamamis
authors: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, United States of America.|Texas A&M Energy Institute, Texas A&M University, College Station, TX, United States of America.|Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United States of America.
authors: Yannis A
authors: YA
authors: Guzman
authors: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, United States of America.|Texas A&M Energy Institute, Texas A&M University, College Station, TX, United States of America.
authors: Melis
authors: M
authors: Onel
authors: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, United States of America.|Texas A&M Energy Institute, Texas A&M University, College Station, TX, United States of America.
authors: Christodoulos A
authors: CA
authors: Floudas
mesh_terms: D004734:Energy Metabolism; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D015497:HIV-1 / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D019713:Receptors, CCR5 / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D013329:Structure-Activity Relationship; D018523:Tropism
chemical_list: C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1