Protein structural disorder of the envelope V3 loop contributes to the switch in human immunodeficiency virus type 1 cell tropism

Jiang, X., Feyertag, F. and Robertson, D. L. (2017) Protein structural disorder of the envelope V3 loop contributes to the switch in human immunodeficiency virus type 1 cell tropism. PLoS ONE, 12(10), e0185790. (doi: 10.1371/journal.pone.0185790) (PMID:29049306) (PMCID:PMC5648111)

Abstract

Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIV’s life cycle, particularly, V3 loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections. Why does this ‘rewiring’ event occur in HIV-1 infected patients? As changes in the charge of the V3 loop are associated with this receptor switch and it has been suggested that charged residues promote structure disorder, we hypothesise that the intrinsic disorder of the V3 loop is permissive to sequence variation thus contributing to the switch in cell tropism. To test this we use three independent data sets of gp120 to analyse V3 loop disorder. We find that the V3 loop of X4 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, while R5X4 virus has the lowest. These results indicate that structural disorder plays an important role in HIV-1 cell tropism and CXCR4 binding. We discuss the potential evolutionary mechanisms leading to the fixation of disorder promoting mutations and the adaptive potential of protein structural disorder in viral host adaptation.

• Item Type: Articles
• Additional Information: FF was supported by a BBSRC studentship and XJ by the MRC (G1001806/1) and WT (097820/Z/11/A) grants to DLR, and by the Issac Newton Trust and WT funding to John Welch, University of Cambridge.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Robertson, Professor David
• Authors: Jiang, X., Feyertag, F., and Robertson, D. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2017 Jiang et al.
• First Published: First published in PLoS ONE 12(10):e0185790
• Publisher Policy: Reproduced under a Creative Commons License