From the thermodynamic point of view, amino acid changes can lead to a change in the internal energy of a protein and induce structural rearrangements. doi: 10.1186/1742-.The rapid growth of un-annotated missense variants poses challenges requiring novel strategies for their interpretation. The co-receptor signaling model of HIV-1 pathogenesis in peripheral CD4 T cells. 1992 66(3):1354–1360.īerger EA, Doms RW, Fenyo EM, Korber BT, Littman DR, Moore JP, Sattentau QJ, Schuitemaker H, Sodroski J, Weiss RA. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. Schuitemaker H, Koot M, Kootstra NA, Dercksen MW, de Goede RE, van Steenwijk RP, Lange JM, Schattenkerk JK, Miedema F, Tersmette M. Replicative capacity, cytopathic effect and cell tropism of HIV. CD4+ NK cells can be productively infected with HIV, leading to downregulation of CD4 expression and changes in function. īernstein HB, Wang G, Plasterer MC, Zack JA, Ramasastry P, Mumenthaler SM, Kitchen CM. Furthermore, the novelty of these computational mutagenesis based predictor attributes distinguishes the models as orthogonal and complementary to previous methods that utilize sequence, structure, and/or evolutionary information. The trained classifiers provide instantaneous and reliable predictions regarding HIV-1 co-receptor usage, requiring only translated V3 loop genotypes as input. Best reported values of sensitivity (85%), specificity (100%), and precision (98%) for predicting X4-capable HIV-1 virus, overall accuracy (97%), Matthew's correlation coefficient (89%), balanced error rate (0.08), and ROC area (0.97) all reach critical thresholds, suggesting that the models outperform six other state-of-the-art methods and come closer to competing with phenotype assays.

An in silico mutagenesis procedure employing multibody statistical potentials, computational geometry, and threading of variant V3 sequences onto an experimental structure, is used to generate a feature vector representation for each variant whose components measure environmental perturbations at corresponding structural positions.Ĭlassifier performance is evaluated based on stratified 10-fold cross-validation, stratified dataset splits (2/3 training, 1/3 validation), and leave-one-out cross-validation. A dataset of 1193 distinct gp120 V3 loop peptide sequences (989 R5-utilizing, 204 X4-capable) is utilized to train predictive classifiers based on implementations of random forest, support vector machine, boosted decision tree, and neural network machine learning algorithms. Determination of HIV-1 affinity for either the R5 or X4 co-receptor on host cells facilitates the inclusion of co-receptor antagonists as a part of patient treatment strategies. HIV-1 targets human cells expressing both the CD4 receptor, which binds the viral envelope glycoprotein gp120, as well as either the CCR5 (R5) or CXCR4 (X4) co-receptors, which interact primarily with the third hypervariable loop (V3 loop) of gp120.

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