Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070, USA.
J Infect Dis. 2010 Feb 15;201(4):618-26. doi: 10.1086/649842.
A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study.
The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters.
Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P = 6.23 X 10(-7)). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 X 10(-6)).
This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis.
未经治疗的人在出现临床艾滋病之前，平均需要 9-10 年的人类免疫缺陷病毒 1（HIV-1）感染才能发展为艾滋病，但个体之间的疾病进展速度有很大差异。为了研究宿主遗传因素对进展为临床艾滋病的速度的影响，我们进行了一项多阶段全基因组关联研究。
发现阶段包括来自多中心艾滋病队列研究的 156 名个体，这些个体是通过富集快速和长期非进展者来增加统计效力而选择的。随后，对来自 HIV-1 感染血清转化者的独立人群的假定相关基因型进行了复制测试。
在位于染色体 1 上 PROX1 上游 36kb 的 1q41 处的单体型中观察到与艾滋病进展延迟相关的显著关联（相对危险比，0.69；Fisher 合并 P=6.23X10(-7)）。在按传播模式分层的分析中进一步复制了这种关联，在性或粘膜和肠外传播中效果一致（相对危险比分别为 0.72 和 0.63，合并 P=1.63X10(-6)）。
本研究鉴定并复制了 PROX1 上游与临床艾滋病进展延迟相关的一个基因座。PROX1 是 T 细胞中干扰素-γ表达的负调节剂，也可减轻血管性肿瘤（如 Kaposi 肉瘤，一种常见的艾滋病定义性恶性肿瘤）的进展。这项研究增加了有效的调节 HIV-1 感染者向临床艾滋病进展的宿主多基因成分，为治疗和改善艾滋病预后提供了潜在的新途径。
