Host-viral interactions are modulated by host-encoding immune response elements and proteins required for the completion of the viral life cycle. A candidate gene approach is being used to identify genes that have a role in viral infection and pathogenesis for four viruses associated with human cancers: the hepatitis viruses B (HBV) and C (HCV); hepatocellular carcinoma (HCC); Epstein-Barr virus (EBV); nasopharyngeal carcinoma (NPC); the human immune deficiency virus (HIV-1); Kaposi sarcoma (KS); and lymphoma. 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 allele and haplotype frequencies between racial groups and between viral strains, together with environmental factors, may explain the geographical variation in infection rates and outcomes observed for HIV-1, EBV, and the hepatitis viruses B and C. We are investigating the role of host genetic variation on disease progression in over 11,000 participants enrolled in HIV-1, HBV and HCV natural history cohort and cross-sectional studies in the USA and China. We are also utilizing a case-control study to identify host factors that influence the development of NPC in Chinese patients infected with EBV. 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 mutations in candidate genes; 3) screen SNPs using high throughput genotyping methods; and 4) use of categorical and survival analyses to test for associations between genotypes and disease phenotypes. Important advances include (1) the identification of a strong regulatory region within intron 1 in the gene encoding the chemokine RANTES, a ligand for the HIV-1 coreceptor, CCR5. Alleles of a SNP (named In1.1 T/C) within the regulator region were found to differentially bind nuclear proteins and regulate transcription: the In1.1 T allele strongly enhanced RANTES transcription, and In1.1 C allele significantly reduced this enhancement. In1.1 C-containing haplotypes, found in 37% of African-Americans, were associated with an accelerated rate of progression to AIDS and AIDS-related death. Both European and African-American carriers for In1.1 C were also at greater risk for HIV-1 infection. (3) The STRL3-3K allele was found to have a protective effect in African-Americans by delaying death in HIV-1-infected individuals with Pneumocystis carinii pneumonia. The pivotal role of IFN-g in immune responses to intracellular pathogens prompted us to look for functional variants in regulatory regions of this highly conserved gene. We identified a SNP IFN-g -179 G/T, in the promoter region that is found in 2-4% of people of African origin or descent but is absent from Caucasians. Using a reporter assay, we have shown that the -179T allele is inducible by TNF-a. The IFN-g -179 G/T genotype was associated with accelerated progression to AIDS (RH=2.34; p=0.009) in African-Americans, possibly because the -179T allele induces CD4+ cell depletion by apoptosis in the presence of TNF-a. We are now investigating the role of this variant on intracelluar and secreted INF-gamma levels in HIV-1 infected and uninfected individuals. Significant progress has been made in the study investigating the role of EBV-associated NPC. We have recruited more than 400 NPC cases, their unaffected spouses who serve as a control, plus a parent or child for haplotype inference. A second case-control study to investigate the role of EBV persistence as determined by the presence of IgA antibody to viral capsid antigen has also been established. The presence of this antibody is a significant risk factor for the development of NPC. Cryopreserved PBMC and non-renewable DNA has been obtained for each study subject. We have genotyped more that 20 candidate genes involved in immune response and inflammation in this cohort. Future plans are to perform a genome scan in an effort to identify haplotypes associated with the NPC and IgA/VCA antibody phenotypes.
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