| Co-Investigator(Kenkyū-buntansha) |
KAWAHARA Sachiyo (TSUJI Sachiyo) Kinki University, School of Medicine, Associate Professor, 医学部, 講師 (60297629)
KANARI Yasuyoshi Kinki University, School of Medicine, Assistant Professor, 医学部, 助手 (60351590)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Research Abstract |
Despite multiple and repeated exposures to HIV-1, some individuals possess no detectable HIV genome and show T-cell memory responses to the viral antigens. HIV-1-reactive mucosal IgA detected in such uninfected individuals suggests their possible immune resistance against HIV acquisition. However, attempts to associate the above HIV-1-exposed but uninfected status with known resistance factors, including the CCR5A32 mutation, have been unsuccessful. Based on the mapping in chromosome 15 of a gene controlling the production of virus-neutralizing antibodies in a mouse model of retrovirus infection, we have reported a strong association between genotypes at marker loci within the syntenic chromosome 22q13.1 region and a putative dominant locus conferring strong anti-HIV-1 immune responses. In this project, we have compared expression levels of all the genes located within the above chromosomal segment utilizing DNA microarrays, and have revealed a higher induction of two particular genes
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in HIV antigen-stimulated peripheral blood mononuclear cells only among the exposed but uninfected, but not in the HIV-infected, individuals. Further, extensive genotyping of single nucleotide polymorphisms (SNPs) and genomic sequencing of the exposed but uninfected and HIV-infected individuals have indicated 1) a significant accumulation of a particular genotype at multiple and mutually linked SNP loci surrounding the above highly induced genes, 2) strong linkage disequilibrium between SNP genotypes across the above two gene loci observed only among the exposed but uninfected individuals, and 3) the presence of possibly functional genetic changes in the putative enhancer element located between the above two genes. Further, the expression of the DNA mutater APOBEC3G genes, whose locus is located in the chromosome 22 in close linkage with the above 22q13.1 segment, was significantly higher among the exposed but uninfected than in HIV-1-infected individuals, and its expression became much higher in CD14^+ monocytes than in other cell-types after the stimulation with interferon-α. Thus, genetically determined resistance against HIV-1 acquisition observed in the HIV-1-exposed but uninfected individuals may be explained, at least partially, by the above observed higher induction of chromosome 22 genes including APOBEC3G. Less
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