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Aim It was recently found that HIV can downregulate HLA-C on infected cells. This is mediated by the viral protein Vpu, and is in addition to the downregulation of HLA-A/B by Nef. The magnitude of HLA-C downregulation varies widely between primary HIV viruses, but the selection pressures resulting in either HLA-C downregulation or preservation are not clear. Methods To better understand viral immune evasion targeting HLA-C, we have characterized HLA-C downregulation by a range of primary HIV-1 viruses. Results 100 replication competent viral isolates, from limiting dilution outgrowth assays of 20 individuals with effective anti-retroviral therapy, show a substantial minority of individuals harbor reservoir virus which strongly downregulates HLA-C. 20 longitudinal samples from 4 untreated individuals demonstrate no changes in HLA-C downregulation during acute infection, but show variation between viral quasispecies that can persist in chronic infection. 200 Vpu molecules cloned from plasma of treatment naive individuals in chronic infection, show that downregulation of HLA-C adapts to host HLA genotype. HLA-C alleles differ in the pressure they exert for viral downregulation of HLA-C, and individuals with higher levels of HLA-C expression favour greater viral downregulation of HLA-C. Studies of primary and mutant molecules show the transmembrane regions of both Vpu and HLA are responsible for their interaction when removing HLA-C from the cell surface. Conclusions Finding that reservoir virus can downregulate HLA-C could have implications for HIV cure therapy approaches in some individuals. The adaptation of HLA-C downregulation to host HLA genotype which is observed, indicates a subset of HLA-C alleles restrict HIV-specific CTL responses which are subverted by viral downregulation of HLA-C. Differential viral modulation of HLA-C, compared to HLA-A/B, can be used to understand differences in the biological roles of these HLA molecules in HIV infection.