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Analyses of host genes that confer immune resistance against human immunodeficiency virus type-1 infection in HIV-1-exposed but uninfected individuals in the overseas cohorts

海外队列中 HIV-1 暴露但未感染个体对人类免疫缺陷病毒 1 型感染具有免疫抵抗力的宿主基因分析

基本信息

批准号：
15406021
负责人：
MIYAZAWA Masaaki
金额：
$ 4.8万
依托单位：
Kinki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Despite multiple and repeated exprosures 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. We tested if the above HIV-1-exprosed but uninfected status was associated with genetic markers other than a homozygous deletion of the CCR5 gene.Based on our mapping in chromosoma 15 of a gene controlling the production of neutralizing antibodies in a mouse retrovirus infection, we genotyped 42 HIV-1-exposed but uninfected Italians at polymorphic loci in the syntenic segment of human chromosome 22, and compared them with 49 HIV-1-infected and 47 uninfected healthy control individuals by a closed testing procedure. A significant association was found between chromosome 22q12-13 genotypes and a putative dominant locus conferring anti-HIV-1 immune responses in the exposed but uninfected individuals. Distributions of linkage disequilibrium across chromosome 22 also differed between the exposed but uninfected and two other phenotypic groups.We next stimulated the peripheral blood mononuclear cells from HIV-1-exposed but uninfected and HIV-1-infected individuals with a mixture of HIV-1 gag and env antigens, and compared the expression of all the genes and open reading frames located in the above candidate region using a DNA microarray technique. Significant induction of several genes at 6 hours after the antigenic stimulation was observed only in the exposed but uninfected individuals. Further linkage of a single nucleotide polymorphism located in one candidate gene with the genotype of the D22S423 marker was observed only in the exposed but uninfected individuals. These data indicated the presence of a new genetic factor associated with the HIV-1-exposed but uninfected status.

尽管多次和反复暴露于HIV-1，一些个体没有可检测到的HIV基因组，并对病毒抗原表现出t细胞记忆反应。在这些未感染的个体中检测到HIV-1反应性粘膜IgA提示他们可能对HIV具有免疫抗性。我们测试了上述hiv -1暴露但未感染的状态是否与CCR5基因纯合缺失以外的遗传标记相关。基于我们在小鼠逆转录病毒感染中控制中和抗体产生的基因15号染色体上的定位，我们在人类22号染色体同染色体段的多态性位点上对42名hiv -1暴露但未感染的意大利人进行了基因分型，并通过封闭测试程序将其与49名hiv -1感染和47名未感染的健康对照个体进行了比较。在暴露但未感染的个体中，发现染色体22q12-13基因型与推定的赋予抗hiv -1免疫应答的显性位点之间存在显著关联。22号染色体上的连锁不平衡分布在暴露但未感染的组和其他两个表型组之间也有所不同。接下来，我们用HIV-1 gag和env抗原的混合物刺激HIV-1暴露但未感染和HIV-1感染个体的外周血单个核细胞，并使用DNA微阵列技术比较位于上述候选区域的所有基因和开放阅读框的表达。在抗原刺激后6小时，仅在暴露但未感染的个体中观察到几个基因的显著诱导。位于一个候选基因上的单核苷酸多态性与D22S423标记基因型的进一步连锁仅在暴露但未感染的个体中观察到。这些数据表明存在与hiv -1暴露但未感染状态相关的新遗传因素。