Effects of genetic variation on infectious disease

我们最近完成的一项研究表明，已知三种不同的HLA等位基因（B*27、B*57和B* 35 Px）在HIV-1感染后的不同时间段内改变艾滋病进展的总体速率。HLA等位基因影响的离散时间提示针对这种动态和慢性免疫抑制疾病的免疫防御的替代功能机制。到目前为止，HLA I类和II类基因分型已经完成了1200个样本从WIHS队列和初步分析的数据表明，有一些显着的特定HLA等位基因和流行的HPV感染以及鳞状上皮内病变之间的关联。我们刚刚开始瓜纳卡斯特HPV队列的基因分型。关于KIR基因的等位基因分析，我们已经在我们的AIDS队列中完成了KIR 3DL 1亚型分型（参见“KIR基因多态性及其在HIV-1发病机制中的作用”），最近在我们的HCV队列中完成了KIR 3DL 1亚型分型。使用在我们实验室分型的正常献血者，我们在NIDDK的合作者发现，来自KIR 2DL 3/HLA-C组1基因型受试者的NK细胞比来自KIR 2DL 1/HLA-C组2受试者的NK细胞对甲型流感病毒感染产生更强的细胞毒性，以及更强和更快的细胞因子产生。这些功能差异可能解释了我们先前报道的KIR 2DL 3/HLA-C组1对HCV的保护性遗传效应。我们对TSG 101的研究现已完成，表明两种非编码单核苷酸多态性（SNP）变异与HIV病毒载量动力学、CD 4 T细胞下降以及感染后艾滋病进展速度的差异相关。我们在5'端区域的-183和+181位点上发现了两个多态性位点，它们分别代表了A、B和C三种单倍型。单倍型C与相对快速的AIDS进展相关，而单倍型B与较慢的疾病进展相关。这两种效应均对中间单倍型A占优势。这些数据提出了一个假设，即TSG 101的非编码变异影响了TSG 101介导的病毒颗粒从感染细胞中释放的效率，从而改变了血浆病毒载量水平和随后的疾病进展。

We recently completed a study showing that three distinct HLA alleles (B*27, B*57 and B*35Px) known to alter the overall rate of AIDS progression act during distinct intervals following HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease. Thus far, HLA class I and class II genotyping have been completed on 1200 samples from the WIHS cohort and preliminary analysis of the data suggests there are a number of significant associations between particular HLA alleles and prevalent HPV infection as well as squamous intraepithelial lesions. We have just begun genotyping of the Guanacaste HPV cohort. With regards to allelic analysis of KIR genes, we have completed KIR3DL1 subtyping in our AIDS cohort (see "KIR gene polymorphism and its role in HIV-1 pathogenesis") and more recently, in our HCV cohort. Using normal blood donors that were typed in our laboratory, our collaborators at the NIDDK have found that NK cells from subjects with the KIR2DL3/HLA-C group 1 genotype exert stronger cytotoxicity, and stronger and more rapid cytokine production in response to influenza A virus infection than NK cells from KIR2DL1/HLA-C group 2 subjects. These functional differences likely explain the protective genetic effect of KIR2DL3/HLA-C group 1 against HCV that we previously reported. Our studies on TSG101, which are now complete, show that two non-coding single nucleotide polymorphism (SNP) variants associate with differences in HIV viral load dynamics, in CD4 T cell decline, and, correspondingly, with rate of AIDS progression after infection. We identified two polymorphic sites in the 5' area located at positions -183 and +181 relative to the translation start, that specify three haplotypes termed A, B, and C. Haplotype C was associated with relatively rapid AIDS progression while haplotype B was associated with slower disease progression. Both effects were dominant over the intermediate haplotype A. The data raise the hypothesis that noncoding variation in TSG101 affects the efficiency of TSG101-mediated release of viral particles from infected cells, thereby altering levels of plasma viral load and subsequent disease progression.