Effects of genetic variation on infectious disease

我们最近完成的一项研究表明，三个不同的HLA等位基因(B*27、B*57和B*35px)在感染HIV-1后的不同时间段内改变了艾滋病的总进展率。HLA等位基因影响的离散时间提示了针对这种动态和慢性免疫抑制疾病的免疫防御的另一种功能机制。到目前为止，来自WIHS队列的1200个样本已经完成了HLAI类和II类基因分型，对数据的初步分析表明，特定的HLA等位基因与流行的HPV感染以及鳞状上皮内病变之间存在许多显著的关联。我们刚刚开始对瓜纳卡斯特人乳头瘤病毒队列进行基因分型。关于KIR基因的等位基因分析，我们已经在我们的艾滋病队列中完成了KIR3DL1亚型(见“KIR基因多态及其在HIV-1发病中的作用”)，最近在我们的丙型肝炎队列中完成了KIR3DL1亚型。我们在NIDDK的合作者使用我们实验室中分型的正常献血者，发现来自KIR2DL3/HLA-C组1基因的受试者的NK细胞比来自KIR2DL1/HLA-C组2的受试者的NK细胞具有更强的细胞毒作用，并且在应对甲型流感病毒感染时产生更强和更快的细胞因子。这些功能差异可能解释了我们先前报道的KIR2DL3/人类白细胞抗原-C组1对丙型肝炎病毒的保护遗传效应。我们对TSG101的研究现已完成，研究表明，两个非编码单核苷酸多态(SNP)变异与HIV病毒载量动态变化、CD4T细胞下降相关，并相应地与感染后AIDS进展速度相关。我们确定了位于5‘端的两个多态位点，分别位于-183和+181位置，分别指定了A、B和C三种单倍型。单倍型C与相对较快的艾滋病进展相关，而单倍型B与较慢的疾病进展相关。这两种效应都主导于中间单倍型A。该数据提出了一种假设，即TSG101的非编码变异会影响TSG101介导的病毒颗粒从感染细胞中释放的效率，从而改变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.