Downregulation of HLA-C shows adaptation to host HLA genotype.

(A) For 186 individuals a single Vpu clone from chronic untreated infection was measured for ability to downregulate HLA-C by transfection of Molt-4 cells. The distribution of HLA-C downregulation is shown, with a threshold of 6-fold used to define 69 strongly downregulating (black) and 117 weakly downregulating Vpu clones (grey). (B) The proportion of Vpu clones that downregulate HLA-C strongly is shown when individuals are stratified by the presence of common alleles of each of the HLA-A,—B, and—C loci. The number of individuals in each group is shown above each plot and statistical analysis is by chi square tests. (C) HLA-C alleles can be grouped as C1 or C2 according to their differential binding of KIR2D receptors, and the proportion of Vpu clones that strongly downregulate HLA-C is shown for individuals when grouped by these genotypes. (D) HLA-C alleles differ in expression level and can be inferred for an individual from the HLA-C genotype. HLA-C expression level and the observed HLA-C downregulation by Vpu are plotted for 186 individuals. (E) For the subset of individuals where viral adaptation to host HLA-C alleles could be quantified (n = 72), the correlation between host HLA-C allele-specific viral sequence adaptation and observed downregulation of HLA-C by Vpu was determined. For 10 HLA-C alleles this correlation is plotted against the proportion of individuals with that HLA-C allele in which Vpu downregulates HLA-C. Correlations were determined using two-tailed Spearman analyses.