HLA-C downregulation by HIV-1 adapts to host HLA genotype

HIV-1 can downregulate HLA-C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV-1 variants. The selection pressures that result in viral downregulation of HLA-C in some individuals, but preservation of surface HLA-C in others are not clear. To better understand viral immune evasion targeting HLA-C, we have characterized HLA-C downregulation by a range of primary HIV-1 viruses. 128 replication competent viral isolates from 19 individuals with effective anti-retroviral therapy, show that a substantial minority of individuals harbor latent reservoir virus which strongly downregulates HLA-C. Untreated infections display no change in HLA-C downregulation during the first 6 months of infection, but variation between viral quasispecies can be detected in chronic infection. Vpu molecules cloned from plasma of 195 treatment naïve individuals in chronic infection demonstrate that downregulation of HLA-C adapts to host HLA genotype. HLA-C alleles differ in the pressure they exert for downregulation, and individuals with higher levels of HLA-C expression favor greater viral downregulation of HLA-C. Studies of primary and mutant molecules identify 5 residues in the transmembrane region of Vpu, and 4 residues in the transmembrane domain of HLA-C, which determine interactions between Vpu and HLA. The observed adaptation of Vpu-mediated downregulation to host genotype indicates that HLA-C alleles differ in likelihood of mediating a CTL response that is subverted by viral downregulation, and that preservation of HLA-C expression is favored in the absence of these responses. Finding that latent reservoir viruses can downregulate HLA-C could have implications for HIV-1 cure therapy approaches in some individuals.Author summary: HLA-C is a member of the major histocompatibility complex class-I (MHC-I) family of molecules which are integral to many responses of innate and adaptive immunity. HIV-1 can downregulate the expression level of HLA-C on infected cells, using the viral protein Vpu, but the magnitude of HLA-C downregulation varies widely between primary HIV viruses. This provides an opportunity to identify opposing pressures on HLA-C expression in infected human individuals. We find that viral downregulation of HLA-C associates with both host and virus genotype, defining allelic differences in HLA-C and Vpu that will help to identify the specific immune responses which result in viral downregulation or preservation of HLA-C. These responses could represent candidates for immune therapy, given their demonstrated effects in vivo. We also find that HIV-1 viruses from the latent reservoir of some individuals can downregulate HLA-C, indicating that in certain individuals HIV-1 cure will require the removal of virus that is able to downregulate HLA-C. The unique role of HLA-C, exerting selection pressures that result in variable modulation of its expression, may make it possible for immunotherapies to achieve enhanced efficacy if both of the opposing pressures on HLA-C expression could be established in the same individual.