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. An estimated 4 million people in the US and 170 million people worldwide are infected with hepatitis C virus (HCV), which is the most common blood-borne infection in the U.S. The vast majority of HCV infections persist and one-third of those with persistent infection will develop chronic liver diseases such as cirrhosis and hepatocellular cancer. Several epidemiological, viral, and host factors have been shown to be associated with HCV clearance or persistence. Notably, a strong immune response to HCV favors viral clearance suggesting that genetic variation in immune response genes might contribute to the differential ability of individuals to clear the virus. A recent genome-wide association study (GWAS) identified a single nucleotide polymorphism (SNP), rs12979860, 3kb upstream of the IL28B gene, which was strongly associated with response to HCV drug treatment. Individuals with the C/C genotype at rs12979860 had a greater than 2-fold rate of sustained virological response (SVR) to HCV drug treatment compared to individuals with the T/T genotype. In order to determine the effects of this SNP on the natural clearance of HCV, we genotyped an existing HCV cohort, made up of people who spontaneously cleared the virus (388 people) or who had persistent infection (620 people). We found that individuals of both European and African ancestry with the C/C genotype were significantly more likely to spontaneously clear the virus. To date, this is the strongest and most significant genetic effect that has been found to associate with spontaneous resolution of HCV infection and points to a principal and fundamental role for IL28B in viral clearance. IL28B produces an antiviral state by triggering a cascade through the JAK-STAT pathway leading to upregulation of the interferon-stimulated genes (ISGs). The mechanism of how the rs12979860 SNP affects IL28B function and the immune response to HCV has not been elucidated. One clue to the mechanism may come from determining whether the SNP affects the outcome of other chronic viral infections where interferons and ISGs are important in the host response, such as hepatitis B virus (HBV) and human immunodeficiency virus-1 (HIV). Given the dichotomous outcomes in both HBV and HIV infections and the importance of interferons and ISGs in these infections, we next tested whether the rs12979860 SNP associates with recovery from an acute HBV infection, resistance to HIV infection, and slower progression of HIV disease. The C/C genotype was not associated with HBV recovery (OR 1.20), resistance to HIV infection (1.04), or HIV disease progression (P greater than 0.05 for all outcomes). These results are in stark contrast to the strong association with HCV outcomes. Thus, the effects of this SNP cannot be generalized to other chronic viral infections. Further studies are needed to understand the mechanisms underlying the beneficial effect of this SNP in HCV infection and how they differ from that in HIV and HBV infections. Variation at the HLA class I locus has a stronger influence on HIV-1 disease outcome than variation found at any other genetic locus identified to date. In support of this finding, genome-wide association studies (GWAS), for which we provided HLA genotypes, provide overwhelming confirmation of the primary role of the MHC in outcome to HIV infection in both Caucasians and African Americans. This observation in humans appears to be true also for rhesus monkeys. We performed statistical analyses that showed that specific MHC class I and II alleles are associated with control of SIV replication in this animal model. These studies were carried out in collaboration with investigators at Duke University (GWAS) and University of Wisconsin (SIV study). We previously showed that HLA-B*35-Px subtypes were associated with accelerated progression to AIDS as compared to the related B*35-PY alleles, but the mechanism for this effect was not defined. In collaboration with investigators from the Ragon Institute of MGH, MIT and Harvard we showed that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory receptor that is expressed on dendritic cells, than does the B*35-PY molecule B*3501. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in vitro and a striking functional impairment of dendritic cells in HIV-1 infected individuals with B*3503. The data provide a novel perspective for the understanding of HLA class I associations with HIV-1 disease progression and for the manupulation of host immunity against HIV-1. Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1 and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1 but the effect of variation at these loci on HIV-2 disease is unknown. We determined HLA class I and KIR gene profiles of a relatively isolated population in Caio, Guinea-Bissau, with one of the highest prevalence rates of HIV-2 infection in the world. The HLA-B*15 alleles B*1503 and B*1510 were observed at a relatively high frequency in this community compared to neighbouring populations. Furthermore, HIV-2-infected individuals with B*1503 (but not B*1510) had significantly higher HIV-2 viral loads and lower CD4 counts compared to those without this allele, suggesting that this allele might be linked to poor control of viral replication and more rapid disease progression. Notably, none of the strongest HLA associations with HIV-1 were observed in our HIV-2 cohort. Interestingly, previous data indicate that HLA-B*1503 associates with low viral loads in HIV-1 clade B-infection, but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. In general, the strongest associations in this study conferred susceptibility to HIV-2 outcomes, while protective factors were quite weak. This observation is contrary to that observed in HIV-1 disease, where the strongest HLA associations confer protection. Perhaps this reflects the less pathogenic nature of HIV-2 and the ability of most HLA class I allotypes to effectively control the virus, as compared to HIV-1, where most allotypes are unable to maintain viral restriction. Our study is the first to provide a detailed analysis of the effects of HLA and KIR genetic variation on resistance/susceptibility to HIV-2 infection and disease progression. 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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