Many studies examining a role for HLA in outcome to HIV-1 exposure and infection have been reported, but the reported associations have often been difficult to affirm in multiple cohorts. Nevertheless, the recurrent implication of certain haplotypes along with the quasi-species pattern of HIV-1 change in infected patients are strong indicators of HLA involvement in HIV-1 pathogenesis. Furthermore, we have typed HIV-1+ hemophiliac sib pairs and observed significantly greater disease concordance in those sharing HLA haplotypes than in those who share no HLA haplotypes. More recently, we have typed the class I genes, HLA-A, -B, and -C, using DNA from 498 individuals, and survival analyses demonstrated a highly significant association of HLA class I homozygosity with rapid progression to AIDS in both Caucasians and African Americans. The effect was apparent for homozygosity at a single HLA class I locus and became more pronounced when two or three class I loci were homozygous. Two alleles, B*35 and Cw*04, showed highly significant association with rapid progression to AIDS. The four individuals homozygous for B*35 and Cw*04 progressed to AIDS within about 5 years, which was quite significant (p=0.0005), in spite of the very low sample size. The effects of zygosity and B*35-Cw*04 on progression to AIDS are stronger than any other genetic associations reported to date. The data set has now been expanded to over 800 individuals and reanalysis of HLA class I effects on AIDS progression is in progress. The host immune response to human papilloma virus (HPV) is thought to be an important determinant of progression to HPV-associated cervical neoplasia. Studies have suggested associations between HLA and cervical neoplasia, but like many studies of HLA and diseases having infectious etiologies, the data reported lack corroboration. We previously typed 711 samples for specific alleles at class I and class II loci that had been shown to have either an increased or decreased risk for cervical disease. Essentially, our data suggested that the alleles HLA-B*07 and DQB1*0302 were positively associated with disease. The haplotype DRB1*1501-DQB1*0602 and the allele DRB1*13 appeared to be protective, as well. We have now begun to type all alleles at HLA class I in this plus an additional study in order to define more precisely the relationship between development of cervical neoplasia and the class I loci. HPV is causally linked to most cervical tumors via binding of its oncoproteins E6 and E7 to tumor suppressor proteins p53 and Rb, respectively. A recent report indicated that a p53 allele characterized by an arginine residue at position 72 (p53Arg) is more efficiently degraded by E6 than the allele containing proline at this same position (p53Pro). To determine the validity of these results in a large epidemiological study, we typed specimens from three distinct cohorts totaling 1,309 women for the p53 variant. We could not confirm the assertion that p53Arg is associated with increased risk of cervical neoplasia in any of the three populations tested and we concluded that this variant does not play a role in susceptibility to cervical neoplasia. More than 90% of adults appear to recover after an acute infection with hepatitis B virus (HBV) as indicated by clearance of hepatitis B surface antigen (HbsAg) from the serum. Most infections acquired in infancy and early childhood persist and individuals with persistent infections are predisposed to hepatic failure and hepatocellular carcinoma. We have investigated the effect of HLA on 31 individuals with persistent HBV infection and 60 controls in a matched case-control study. The combination of the class II alleles DQA1*0501 and DQB1*0301 (which are in strong linkage disequilibrium) showed a significant association with risk for disease (OR=3, p=0.005), as did the three locus combination of DQA1*0501, DQB1*0301, and DRB1*1102 (OR=10.7, p=0.01). An expansion of this study is underway. Hepatitis C virus (HCV) is the most common bloodborne infection in the United States with estimates of 4 million HCV-infected persons in the U.S. and 170 million worldwide. In contrast to HBV, viremia persists in 85% and is cleared in 15% of acutely-infected individuals. In general, clearance occurs 3-24 months after infection and is rare thereafter. This dichotomy in outcome serves as the basis for host genetic studies of HCV outcomes. Some individuals with persistent infection will develop life-threatening complications of cirrhosis or hepatocellular carcinoma. About 5-25% of persistent infections will develop into cirrhosis 10-20 years after infection. Typing of HLA class I and class II on 109 clearance cases and 218 matched controls who have persistent infection is presently underway. Role of HLA in AIDS Outcome to HIV-1 Exposure - AIDS, HIV, HLA, - Human Tissues, Fluids, Cells, etc.
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