Over the past decade HLA-C, the least polymorphic classical HLA class-I molecule, has been found to influence HIV-1 disease. Early genome-wide association studies identified a strong effect of a variant marking HLA-C in the outcome of HIV-1 infection. It was determined that HLA-C alleles vary in expression level, which correlate inversely with HV-1 viral load, suggesting higher HLA-C expression can be disadvantageous for the virus. It was then found that HLA-C is downregulated on infected cells by most primary clones of HIV-1, and that downregulation of HLA-C is mediated by the Vpu protein of HIV-1. These findings modify a dogma in the field, that HIV-1 downregulates HLA-A/B to evade CTL, but preserves HLA-C expression to inhibit NK cells. Vpu mediated downregulation of HLA molecules raises new questions, and enables novel approaches to investigate HIV immune-evasion. The specific immune responses which select for viral modulation of HLA-C are not known, but this can be investigated by comparing host immunity between patients in which HIV-1 shows weak versus strong HLA-C downregulation, because the magnitude of HLA-C downregulation varies widely between primary viruses in contrast to downregulation of HLA-A/B by Nef.
The pilot study hypothesizes that in some individuals or times of infection, HLA-C restricted HIV-specific CTL dominate selection pressure on the virus through HLA-C, and are subverted by downregulation of HLA-C. At other times NK cells, governed by inhibitory receptors for HLA-C, may dominate the selection pressure and be evaded by adaptation of Vpu to preserve HLA-C expression. The study proposes two aims to determine correlates of the variation between HIV-1 viruses in HLA-C downregulation, which could indicate the functional basis for viral downregulation of HLA-C. Aim 1, addressing host genetic differences, will use a large cohort of ART-naïve HIV-1 patients in which host and viral genotypes have been determined. Tested will be if HLA-C downregulation by Vpu clones shows adaptation to host HLA/KIR genotypes that indicate NK or CTL responses. Aim 2, to identify immune response correlates of HLA-C downregulation, will use a resource of multiple clonal isolates that have been isolated from individual HIV patients. Compared will be HIV-specific HLA-C restricted CTL responses between patients that show distinct patterns of HLA-C downregulation. By determining the functional basis for viral downregulation of HLA-C by Vpu, the aim is to develop understanding of this novel immune evasion activity, which has potential to influence strategies for HIV cure.