HIV-1 is known to downregulate the HLA-C on infected cells by using the viral protein Vpu. However, the magnitude of this downregulation appears to vary substantially between primary HIV variants, and it is not clear what selection pressures are leading to viral downregulation of HLA-C in some patients but not others. Therefore the authors sought to characterise the extent of HLA-C downregulation caused by a range of primary HIV. By looking at 128 replication competent viral isolates from 19 patients being effectively treated with antiretrovirals, the authors found that a substantial minority of patients do have latent reservoir viruses that strongly downregulate HLA-C. Untreated infections did not display any change in HLA-C downregulation during the first 6 months of infection, but variation between viral quasispecies can be detected in chronic infection. When Vpu molecules were cloned from the plasma of 195 treatment-naïve patients with chronic infection, they found that downregulation of HLA-C does adapt to the host HLA genotype. HLA-C alleles were found to differ in the pressure they exert for downregulation and patients with higher levels of HLA-C expression were also found to favour greater viral downregulation of HLA-C. The authors were able to identify five residues in the transmembrane region of Vpu and four residues in the transmembrane domain of HLA-C that appear to determine the interactions between Vpu and HLA. This observed adaptation of Vpu-mediated downregulation to host genotype indicates that HLA-C alleles differ in their likelihood of mediating a CTL response that is subverted by viral downregulation, and that preservation of HLA-C expression is favoured in the absence of these responses. Therefore this finding that latent reservoir viruses can downregulate HLA-C has future implications when considering approaches to curing HIV-1 infection.
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