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. The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligandreceptor interactions with killer-cell immunoglobulin-like receptors. While higher expression levels of HLA-C are protective against viral load control in human immunodeficiency virus (HIV) infected individuals, the mechanism for variable expression of HLA-C alleles is not known. We identified a polymorphic microRNA (miRNA) target site in the 3 untranslated region (3UTR) of HLA-C. Common single nucleotide polymorphisms in the miRNA binding site regulate binding of miRNA and subsequent post-transcriptional processing of the RNA, thus resulting in high or low HLA-C expression. A significant protective effect against HIV was observed amongst the group of HLA-C alleles that escape miRNA-mediated downregulation potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease. Despite the potential role of HLA class II alleles in HIV infection, only a limited number of alleles have been associated with HIV disease outcome. In particular, several DRB1*13 alleles and the DRB1*13-DQB1*06 haplotype have been reported to confer a certain degree of protection, but all of these reports focused on highly selected patient subsets, including long-term nonprogressors, subjects treated during acute infection, and children with vertically transmitted HIV. The role of HLA class II alleles in chronic progressive HIV infection remains unknown. To investigate the effect of HLA class II alleles on disease progression in chronic HIV infection, we studied a well-characterized cohort of 426 antiretroviral therapy (ART)naive, HIV-1 clade C infected, mainly female black South Africans, as well as 1436 HIV-1 clade B virusinfected persons from the Multicenter AIDS Cohort Study (MACS). We found that the DRB1*1303 allele is associated with reduced viral loads in both B and C clade populations. The observation that DRB1*13 confers protection has been shown in other infections including hepatitis B virus infection and human papillomavirus (HPV) infection. It remains uncertain, however, whether the observed associations can be attributed to a stronger and more effective T cell response or whether other mechanisms mediate the DRB1*13 effect. There is substantial interperson variability in the virus load set point, with most individuals having stable levels exceeding 10,000 RNA copies/ml. Yet a small number of people demonstrate sustained ability to control HIV replication without therapy. Such individuals, referred to as HIV controllers, typically maintain stable CD4+ cell counts, do not develop clinical disease, and are less likely to transmit HIV to others. To define host genetic effects on the outcome of chronic HIV infection, as part of the International HIV controllers study, we took part in a genome-wide association analysis of a multiethnic cohort of HIV-1 controllers and progressors. More than 300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC were identified and none elsewhere. Further analysis indicated that specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, could explain the SNP associations and reconcile previously identified protective and risk HLA alleles. The combination and location of the significant amino acids defined in this study implicate the nature of the HLA viral peptide interaction as the major genetic factor modulating durable control of HIV infection and provide the basis for future studies of the impact of HLA-peptide conformation on immune cell induction and function. The natural history of hepatitis C virus (HCV) infection is highly variable. Approximately 20 to 30 percent of individuals clear HCV spontaneously after acute infection, and only a subset of those with persistent HCV infection develop progressive liver disease. Recent epidemiologic studies have shown strong associations between HLA genotype and spontaneous clearance of HCV, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection. We performed high-resolution HLA class I and II genotyping in a prospective cohort of 519 HIV-seropositive and 100 HIV-seronegative women with persistent HCV infection. DQB1*0301 was associated with low baseline HCV load, as well as with low odds of liver fibrosis at baseline and/or during follow-up. Thus, HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies. Inherited genetic polymorphisms within immune response genes have been shown to associate with risk of invasive cervical cancer (ICC) and its immediate precursor, cervical intraepithelial neoplasia grade 3. We used the transmission/disequilibrium test to detect disease-liability alleles and investigate haplotype transmission of KIR and HLA class I polymorphisms in a large family-based population of women with cervical cancer and their biological parents (359 trios). The effect of distinct human papillomavirus types was also explored. HLA-Cw group 1 (HLA-Cw alleles with asparagine at position 80), which serves as ligand for certain killer immunoglobulin-like receptors (KIR), was significantly overtransmitted in women with ICC (P = 0.04), and particularly in the subgroup of women infected with high risk HPV16 or 18 subtypes (P = 0.008). These data support the involvement of the HLA-C locus in modulating the risk of cervical neoplasia perhaps through its function as ligands for KIR, but functional studies are essential to confirm this hypothesis. Natural killer (NK) cells have an important role in the control of viral infections. Epidemiological and functional studies have suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory KIR. However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. In collaboration with our colleagues from the Regan Institute we showed that KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4+ T cells, and reduce the antiviral activity of KIR-positive 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 was previously 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010791-05
Application #
8349164
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$1,003,946
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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