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bioRxiv · 10.1101/130161

Protein Structural Disorder Of The Envelope V3 Loop Contributes To The Switch In Human Immunodeficiency Virus Type 1 Cell Tropism

Jiang, X.·Feyertag, F.·Robertson, D. L.
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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 HIVs 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 plays a role in determining 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 determining HIV-1 cell tropism and CXCR4 binding. We speculate that changes in N-linked glycosylation associated with tropism change (from R5 to X4) are required to stabilise the V3 loop with increased disorder tendency during HIV-1 evolution. 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.\n\nIMPORTANCEHIV-1 cell entry relies on the V3 loop of its heavily glycosylated envelope protein gp120 to bind to a host coreceptor CCR5 or CXCR4. Unraveling the mechanism whereby HIV-1 switches host coreceptor is critical to understanding HIV-1 pathogenesis and development of novel intervention strategies. However, a mechanistic understanding of the switch is limited as no gp120-CCR5/CXCR4 complex is available, due to the intrinsically disordered nature of the V3 loop responsible for coreceotor swtich. We hypothesise that shifts of V3 disorder may contribute to HIV-1 coreceptor switch and cell tropism. In this study we compared the disorder tendency of the V3 loop before and after the coreceptor switch. We find that the coreceptor switch is associated with a significant increase of V3 loop disorder from CCR5 to CXCR4 using. This result provides a mechanistic explanation of coreceptor switch that increasingly disordered V3 loop results in use of a different host coreceptor.

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Jiang, X., Feyertag, F., Robertson, D. L.. 2017-04-24. Protein Structural Disorder Of The Envelope V3 Loop Contributes To The Switch In Human Immunodeficiency Virus Type 1 Cell Tropism. https://doi.org/10.1101/130161

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