HLA-C downregulation by HIV-1 adapts to host HLA genotype
Fig 4
Variation in the Vpu transmembrane region is responsible for the range of HLA-C downregulation exhibited by primary HIV-1 viruses.
(A) Sequence of representative Vpu clones that weakly (clone 1), or strongly downregulate HLA-C (clones 2–4), are shown aligned to Vpu from NL4-3. (B) A multiple linear regression model using 191 of the primary Vpu clones identifies 5 positions of Vpu at which the residues indicated associate independently with HLA-C downregulation. (C) These positions were each confirmed to influence HLA-C downregulation using single residue mutants of Vpu. HLA-C staining is shown for cells transfected with primary Vpu clones (red), single residue mutants (black), and untransfected cells (grey). (D) HLA-C staining for cells transfected with a Vpu constructed to have all 5 residues associated with HLA-C downregulation (red), or that with no residues associating with HLA-C downregulation (black), is shown compared to untransfected control (light grey). (E) HLA-C downregulation predicted by the model in panel B, compared to that observed for each of the 191 Vpu clones. (F) An NMR structure of Vpu, with N-terminal and transmembrane regions highlighted, shows the location of the 5 Vpu positions at which primary sequence variations associate with HLA-C downregulation (green).