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. Allotypes of the NK cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their HLA-B Bw4 ligands present on target cells. Using a sample size of over 1500 HIV+ individuals, we showed that multiple distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA levels in a consistent manner. Inhibitory KIR3DL1 alleles were grouped based on distinct functional characteristics. Previous data have indicated a functional distinction between alleles that are strongly inhibitory and those that are weakly inhibitory. Overall, a pattern emerged indicating relatively strong protection through strongly inhibitory KIR3DL1 alleles + HLA-B alleles with the Bw4-80I motif and a weak protective effect through weakly inhibitory KIR3DL1 alleles + HLA-B alleles with the Bw4-80T motif. These data were reinforced by parallel conclusions when the individual HLA-B*57 (Bw4-80I) and HLA-B*27 (Bw4-80T) alleles were examined and shown to be most protective in the presence of strongly inhibitory KIR3DL1 alleles and weakly inhibitory KIR3DL1 alleles respectively. An analysis of mean viral load data determined from a group of 901 individuals, showed protective effects of the various KIR3DL1/HLA-B genotypes remarkably consistent with those observed in disease progression analyses. Thus, the influence of these genotypes on disease course occurs early after infection, and may continue throughout the chronic phase of infection. The protection against AIDS progression conferred by various combinations of KIR3DL1/Bw4 genotypes shown in this study represents the first data to support a consequential impact of differential KIR3DL1 allotypic functions on disease outcome of any sort and suggest that NK cells play a critical role in the natural history of HIV infection. Because HLA-B alleles influence HIV-1 disease progression and viral levels, we hypothesized that they might also influence HIV-1 transmission. In order to investigate if the presence of HLA-B alleles with the Bw4 epitope in HIV-1-infected men decreased the risk of transmission to their female sex partners we studied 304 HIV-1-infected men with hemophilia and 325 female sex partners. Among the 325 women, 44 (13.5%) were infected with HIV-1. HIV-1 infection in the women was associated with the HLA-B genotype of their male partner. Compared with men who were homozygous for Bw6, men who carried Bw4 were about half as likely to have transmitted HIV-1 to their female partner (OR, 0.52; 95% CI, 0.27-0.98; P = 0.04). We concluded that the presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission, which suggests that these alleles reduce infectivity for HIV-1. We have also provided genotyping data for studies in which the functional significance of HLA class I polymorphism on HIV resistance was tested. We have begun to make a concerted effort to support collaborators who are characterizing the differential protection conferred by HLA class I allotypes against HIV. Some of these studies indicate that strong innate and acquired immune responses during the early phase of infection are especially important in maintaining control over HIV during the chronic phase. KIR3DL1 is a highly polymorphic gene with more than 40 alleles described so far, including its activating counterpart, KIR3DS1. We have previously shown that KIR3DS1 associates with slow progression to AIDS in individuals who also have HLA B Bw4 encoding isoleucine at position 80. However, due to the lack of a KIR3DS1 specific antibody, expression and function have never been reported. In collaboration with another group in the LEI we have now demonstrated KIR3DS1 expression on a substantial subset of peripheral NK cells using the monoclonal antibody Z27 (which also recognizes KIR3DL1). The fidelity of this detection method was confirmed by analysis of KIR3DS1 transfectants and through the identification of a novel KIR3DS1 allele that is prematurely truncated and not expressed on the cell surface. In addition, ligation of KIR3DS1 by Z27 leads to NK cell interferon gamma production and degranulation as assessed by expression of CD107a. The high frequency of KIR3DS1 expression, together with its ability to activate NK cells begin to address the epidemiological data suggesting a critical role for this receptor in HIV pathogenesis. We have also participated in studies aimed at determining the ligand for KIR3DS1 and viral peptide specificity in the interaction between KIR3DL1 and HLA-B Bw4. Using tetramer technology established in Dr. Sarah Rowland-Jones laboratory, we have shown that KIR3DL1 subtypes bind Bw4 tetramers in a peptide-specific manner. While our original attempts to identify ligands for KIR3DS1 have been unsuccessful, we are pursuing this work with promising preliminary results. Recovery from acute hepatitis B virus (HBV) infection requires a broad, vigorous T-cell response, which is enhanced in mice when chemokine receptor 5 (CCR5) is missing. To test the hypothesis that production of a nonfunctional CCR5 (CCR5Δ32 [a functionally null allele containing a 32-bp deletion]) increases the likelihood of recovery from hepatitis B in humans, the group studied 526 persons from three cohorts in which one person with HBV persistence was matched to two persons who recovered from an HBV infection. Genotyping for CCR5Δ32 and for polymorphisms in the CCR5 promoter and in coding regions of the neighboring genes, chemokine receptor 2 (CCR2) and chemokine receptor-like 2 (CCRL2) was performed. Allele and haplotype frequencies were compared among 190 persons with viral recovery and 336 with persistent infection by use of conditional logistic regression. CCR5Δ32 reduced the risk of developing a persistent HBV infection by nearly half (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33 to 0.83; P = 0.006). This association was virtually identical in persons with and without a concomitant human immunodeficiency virus infection. Of the nine individuals who were homozygous for the deletion, eight recovered from infection (OR, 0.25; 95% CI, 0.03 to 1.99; P = 0.19). Although other relevant genes have been identified previously, this deletion is important since it is present in 13% of people who recovered and it has one of the strongest odds ratios published to date. None of the other neighboring polymorphisms examined were associated with HBV outcome. These data demonstrate a protective effect of CCR5Δ32 in recovery from an HBV infection and provide genetic epidemiological evidence for a role of CCR5 in the immune response to HBV. Further, the fact that the findings support data from mouse models showing an increased T-cell response to other infectious agents with CCR5 deficiency is particularly intriguing because it offers a potential means to enhance the T-cell response to HBV by [summary truncated at 7800 characters]
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