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.
Highlights
Human immunodeficiency virus type 1 (HIV-1) cell entry relies primarily on the binding of viral envelope protein, gp120, to two host immune cell membrane proteins, namely, the CD4 receptor and the coreceptor CCR5 or CXCR4 [1]
Note that Geno2pheno does not distinguish between X4 and R5X4 viruses, this means that sequences classed as true could be either X4- or dual-tropic, which has important implications when interpreting the statistical test results
We calculated the disorder tendency of amino acids in the full-length consensus envelope protein sequences of receptors CCR5 (R5), R5X4 and X4 tropic viruses by four different methods, respectively. This allowed us to obtain an overview of the extent of protein disorder in HIV-1 envelope proteins by tropism with different methods
Summary
HIV-1 cell entry relies primarily on the binding of viral envelope protein, gp120, to two host immune cell membrane proteins, namely, the CD4 receptor and the coreceptor CCR5 or CXCR4 [1]. Virus that solely uses CCR5 as coreceptor is termed R5 tropic, whereas exclusive CXCR4 using virus is termed X4 tropic, while virus that can use both coreceptors for cell entry is termed dual tropic (R5X4). The switch from CCR5 to CXCR4 is correlated with disease progression and pathogenesis [2, 3]. The CCR5 receptor is not expressed in individuals that present the CCR5 delta-32 mutation [4].
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