The extensive variation at some of the immune response genes is central amongst the host genetic determinants that contribute to the variability in risk of virtually all human diseases. We have studied the genetic effects of the highly polymorphic KIR and HLA loci, as well as other related, less polymorphic loci on several diseases. Our contributions to the general understanding of these effects are summarized here.Several reports have pointed to variation in the human leukocyte antigen (HLA) class I and II genes as determinants of outcome after HBV infection. Recently the importance of HLA genes was further highlighted by the first genome-wide association study (GWAS) in Asian patients with chronic hepatitis B, where variants near the HLA-DP gene showed the strongest genome-wide association with chronic HBV infection and HBV recovery/persistence. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3 untranslated regions (3UTRs) in a cohort of 662 individuals of European-American and African-American ancestry. The GWAS variant (rs9277535;550A/G) in the 3UTR of the HLA-DPB1 gene that associated most significantly with outcome to HBV infection in Asians had only a marginal effect on HBV recovery in the European- and African-American samples tested (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). We further determined that the 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1 04:01) from the most susceptible (DPB1 01:01), whereas 550A/G does not. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection. The results strongly implicate the 3UTR region of HLA-DP with HLA-DP expression and outcomes of HBV infection. However it will be necessary to determine the mechanism for varied expression of HLA-DP, which may involve regulation through differential microRNA activity as was previously shown for HLA-C by the group. If HLA-DP expression levels do indeed explain the association between HLA-DP and HBV disease pathogenesis, further work will be required to determine how varied expression of this molecule at the site of infection in the liver is affecting the immune response to HBV.There is marked intrinsic variation in the extent to which individuals are able to control HIV-1. Along with our collaborators from Duke University we identified a genetic copy number variable region (CNV) that plays a significant role in the control of HIV-1. This CNV is located in the genomic region that encodes the killer cell immunoglobulin-like receptors (KIRs) and specifically affects the KIR3DS1 and KIR3DL1 genes. Using both genetic association and functional evidence we demonstrated that increasing gene counts for KIR3DL1 confer increasing levels of protection against HIV-1, but only in the presence of at least one copy of KIR3DS1. This effect was associated with a dramatic increase in the abundance of KIR3DS1+ NK cells in the peripheral blood, and strongly associated with a more robust capacity of peripheral NK cells to suppress HIV-1 replication in vitro. This work provides one of the few examples of an association between a relatively common CNV and a human complex trait. There is strong evidence for selection pressure of CD8+ T cells on HIV sequence evolution over the course of infection. Following the peak in CD8+ T cell response the virus begins to show dramatic changes in sequence. It is now becoming apparent that NK cells can also mediate immune pressure on the virus in part via KIR-associated HIV-1 sequence polymorphisms. A collaborative effort with investigators from the Ragon Institute identified several amino acid polymorphisms within the HIV-1 sequence that were significantly associated with the presence of specific KIR genes. Functional analyses showed that polymorphisms in a region encoding the carboxy-terminal end of Vpu and the amino-terminal end of Env enhanced the binding of the inhibitory KIR2DL2 to HIV-1 infected targets, thereby reducing the antiviral activity of NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as has been described for virus-specific T cells and neutralizing antibodies. NK cells might therefore have a previously underappreciated role in contributing to viral evolution.Genetic diversity of immune response genes, such as HLA and KIR loci, holds promise for explaining, in large part, the variability in outcome to viral infection amongst exposed individuals. Understanding how this diversity influences the immune response presents new opportunities for development of effective therapeutics and vaccines, justifying close scrutiny of these genes in viral infections.
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