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

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.