Effects of genetic polymorphism in MHC, KIR, and related loci on human disease

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We have begun to test for associations between HLA variation and publicly available data on responses to immune checkpoint inhibitors (ICI) across a number of cancer types. It was recently demonstrated that homozygosity at HLA class I associates with poor response to checkpoint blockade immunotherapy, which parallels our earlier findings on a deleterious effect of homozygosity on HIV disease progression. Homozygosity theoretically limits the peptide repertoire presented to CTL, resulting in overall weaker immune responses compared to that in people with more diverse class I genotypes. We have used publicly available data from a previous study, which includes 1535 advanced cancer patients treated with drugs targeting CTLA4 and or PD1, PDL1, in order to investigate more thoroughly the influence of HLA class I variation on immunotherapy. We observed an association between HLA A03 and poor response to checkpoint blockade immunotherapy among combined cancer cell types, and HLA A0301 homozygosity has a stronger effect than homozygosity for any other HLA A allele. The effect was more pronounced if patients with melanoma and non-small cell lung cancer were excluded, suggesting that HLA effects are likely to be cancer type specific to some extent. We will attempt to validate these findings in an independent cohort and determine which cancers are driving the effect. This line of research, which we intend to continue more rigorously, could help predict which patients are more or less likely to respond to checkpoint blockade immunotherapy. We have begun to work with clinicians in the NIH Clinical Center to gain access to materials in their trials of ICI therapy so that we can study these effects in much greater detail. We will have access to DNA from the NCI trials along with matched clinical and genetic data, the likes of which are not available in public databases. HIV1 can downregulate HLA C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV1 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 HIV1 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 naive 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 HIV1 cure therapy approaches in some individuals. The chemokine receptor gene cluster on human chromosome 3 encodes the primary co-receptor for HIV, CCR5. Multiple genomewide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV coreceptor CCR5, but the functional basis for the strongest of these associations, rs1015164AG, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4 T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3'untranslated region, protecting CCR5 messenger RNA from Raly mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4 T cells with CCR5 tropic HIV in vitro. These data represent a rare determination of the functional importance of a genomewide disease association where expression of a lncRNA affects HIV infection and disease progression.