This analysis shows that, in patients with HIV-1 infection, a single amino acid change in HLA molecules has a substantial effect on the rate of progression to AIDS. The different consequences of HLA-B*35-PY and HLA-B*35-Px in terms of disease progression highlight the importance of the epitope specificities of closely related class I molecules in the immune defense against HIV-1.

In studies of acute hepatitis C virus (HCV) infectionHepatitis C virus (HCV) is an important blood-borne pathogen that is eliminated from the host in approximately 15% of acutely infected individuals while persisting in the remaining 85% of acutely infected individuals (1, 26). The factors involved in viral clearance are not understood, but many studies suggest host differences are critical. Of 704 Irish women who were accidentally infected with the same viral inoculum (contaminated immunoglobulin D antibody), 314 (45%) cleared their infection (13). Likewise, 43% of 152 German women cleared their infection after being exposed to the same contaminated lot of immunoglobulin D antibody (16). Since the women in their respective studies received the same virus, viral diversity cannot account for the dichotomy in outcome, rather differences in host response were likely the determining factor. Another study found marked differences in the frequency of viral clearance in Caucasians and African-Americans (21). The breadth and vigor of the host cellular immune response correlated with viral clearance in a study of six chimpanzees (6). Similarly, studies in humans have shown that a stronger polyclonal cytotoxic T lymphocyte (CTL) response is associated with viral clearance (18).The class I and class II human leukocyte antigens (HLA) are central to the host immune response and thus are ideal candidate genes to investigate for associations with HCV outcomes. Class I and class II HLA are encoded by the most polymorphic genes known and present antigen to CD8 ϩ cytotoxic T cells and CD4 ϩ helper T cells, respectively. Polymorphisms in the peptide binding regions of these molecules determine antigenic specificities and the strength of the immune response to a given pathogen. Certain HLA alleles have been shown to influence the outcome of other chronic viral infections (12,19,23), and a few recent studies examined class II HLA alleles in the context of HCV clearance (3,20,22,25). Given the importance of the cellular immune response in HCV infection, it is reasonable to postulate that certain HLA class I molecules may present HCV epitopes to cytotoxic T cells, resulting in a protective immune response, whereas other types may participate less efficiently in clearance of the virus. To date, this hypothesis has not been investigated; thus, using three distinct cohorts of individuals, we examined whether particular HLA class I alleles are predisposing factors to either HCV clearance or persistence.

A broad, vigorous CD4 T cell response, mediated by class II human leukocyte antigens (HLAs), favors hepatitis C virus (HCV) clearance. HLA-DQB1*0301 has been associated with viral clearance in an ethnically homogeneous cohort. To validate this association and to identify other class II associations in an ethnically varied cohort, molecular class II HLA typing was performed on 200 HCV clearance and 374 matched persistently infected subjects. HLA-DQB1*0301 was weakly associated with viral clearance in combined ethnic groups (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.53-0.97) but was stronger in black subjects. In white subjects, viral clearance was associated with DRB1*0101 (OR, 0.32; 95% CI, 0.17-0.60) and its DQB1*0501 haplotype, whereas viral persistence was associated with DRB1*0301 (OR, 2.36; 95% CI, 1.23-4.52) and its DQB1*0201 haplotype. These results support a role for class II alleles in the immune response to HCV and underscore the importance of studying genetic associations in an ethnically diverse cohort.

Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by

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