Analysis of Physicochemical and Structural Properties Determining HIV-1 Coreceptor Usage

Katarzyna Bozek,Rolf Kaiser,Thomas Lengauer,Saleta Sierra,Francisco S Domingues,Sergei L Kosakovsky Pond

doi:10.1371/journal.pcbi.1002977

Abstract

The relationship of HIV tropism with disease progression and the recent development of CCR5-blocking drugs underscore the importance of monitoring virus coreceptor usage. As an alternative to costly phenotypic assays, computational methods aim at predicting virus tropism based on the sequence and structure of the V3 loop of the virus gp120 protein. Here we present a numerical descriptor of the V3 loop encoding its physicochemical and structural properties. The descriptor allows for structure-based prediction of HIV tropism and identification of properties of the V3 loop that are crucial for coreceptor usage. Use of the proposed descriptor for prediction results in a statistically significant improvement over the prediction based solely on V3 sequence with 3 percentage points improvement in AUC and 7 percentage points in sensitivity at the specificity of the 11/25 rule (95%). We additionally assessed the predictive power of the new method on clinically derived ‘bulk’ sequence data and obtained a statistically significant improvement in AUC of 3 percentage points over sequence-based prediction. Furthermore, we demonstrated the capacity of our method to predict therapy outcome by applying it to 53 samples from patients undergoing Maraviroc therapy. The analysis of structural features of the loop informative of tropism indicates the importance of two loop regions and their physicochemical properties. The regions are located on opposite strands of the loop stem and the respective features are predominantly charge-, hydrophobicity- and structure-related. These regions are in close proximity in the bound conformation of the loop potentially forming a site determinant for the coreceptor binding. The method is available via server under http://structure.bioinf.mpi-inf.mpg.de/.

Highlights

The entry of the human immunodeficiency virus (HIV) into human cells is initiated by binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor [1,2]
Monitoring HIV tropism is of high importance due to the relationship of the emergence of CXCR4-tropic virus with the progression of immunodeficiency and for patient treatment with the recently developed CCR5 antagonists
Computational methods for predicting HIV tropism are based on sequence and on structure of the third variable region (V3 loop) of the viral gp120 protein — the major determinant of the HIV tropism

Summary

Introduction

The entry of the human immunodeficiency virus (HIV) into human cells is initiated by binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor [1,2]. This primary interaction induces conformational changes in gp120 [3] that enable viral binding to one of the cell-surface coreceptors CCR5 or CXCR4 [4]. Whether a virus can bind to CCR5 only (R5 virus), or is capable of binding to CXCR4 (X4 virus) is determined predominantly by the sequence and structure of this region [7].

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Discussion

Conclusion