Host-viral interactions are modulated by host genes encoding immune response elements and by host proteins required for the successful completion of the pathogen's lifecycle. A candidate gene approach to identify polymorphic loci is being used to identify genes that have a role in viral infection pathogenesis. Identification of such loci provides a valuable tool for the identification of host-cellular components that are operative in viral infection, replication, viral assembly, and immune regulation of the infection. Defining the mechanisms by which host factors restrict viral disease processes will advance our understanding of viral pathogenesis and may lead to possible therapeutic interventions. Differences in mutation frequencies between ethnic/racial groups may also explain at least in part the geographical variation observed for the HIV and hepatitis viruses B and C (HBV and HCV). We are investigating the role of host genetic variation on disease progression in over 7000 participants enrolled in HIV, HBV and HCV natural history cohort studies in the USA and China. Our approach has been to: 1) establish cell lines from study participants as a renewable source of DNA; 2) identify single nucleotide polymorphisms (SNPs) or insertion/deletion (indel) mutations in candidate genes; 3) screen SNPs using high throughput genotyping methods; and 4) use categorical and survival analyses to test for associations between genotypes and disease phenotypes.Polymorphisms in the promoter region of the gene encoding RANTES, a ligand for the HIV-1 coreceptor, are associated with modulation of AIDS progression. Haplotype analysis has revealed that a novel intron variant is either tracking the functional site or modifies the effect of two promoter variants. In a systematic screen of genes encoding 5 chemokine receptors that bind to HIV-1 in vitro, we have identified 6 SNPs in functional or coding regions of the genes. Although these markers are not associated with HIV pathogenesis, they may be important markers in inflammatory diseases such as asthma and arthritis. The candidate gene approach has led to the identification of at least ten genetic variants that affect HIV infection and pathology. Although the effect of each of these variants is small, together they account for approximately 30-50% of long-term AIDS survivors.Using the genetic analysis of HIV-1 as a model for association analysis of complex diseases which have both genetic and environmental components, we are employing a similar strategy to investigate the host genetic contributions to outcomes following infection with the hepatitis viruses, HCV and HBV. These important human viral infections have global distributions and extremely high prevalence rate in some regions of the world and among certain risk groups and cause considerable morbidity and mortality. They are also associated with increased risk of liver cancer, and have similar, although not identical, risk factors. Because pathogenic effects of these viruses are highly variable and not fully explained by strain differences or subtypes, it is plausable that differential outcomes to exposure have a genetic basis. We are currently accruing patients for case control studies to identify candidate genes which effect viral clearance, progression to cirrhosis, and resistance to infection for these important pathogens. Identification of Candidate Gene Polymorphisms Associated with AIDS and Hepatitis
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