Host Genomic Factors in Infectious Disease Susceptibility

尽管对感染的流行病学和行为危险因素有了透彻的了解，但世界范围内的艾滋病毒感染率仍然非常高。这些风险因素具有多种性质，包括高风险的性行为、艾滋病毒的地理流行情况、传播者的病毒载量、包皮环切状况和其他性传播感染，如单纯疱疹病毒2型感染。然而，在非常相似的风险环境中，只有一些人感染，而另一些人没有感染，这一观察结果仍然有些令人费解。在这个项目中，我们的目标是使用新的精确GWAS方法来发现宿主基因组多态性，这些多态性决定了对HIV感染的保护和易感性。我们对高风险的HVTN 505疫苗队列进行了两阶段的完全基于ngs的分析，并对来自其他队列的hiv感染者进行了仔细匹配。我们使用我们的数据集来探索HVTN 505试验中宿主遗传对疫苗效力影响的单独附加问题。我们发现了多个具有非常重要意义的多态性，这些多态性决定了对HIV感染的保护和易感性。我们发现HVTN 505在30%的具有特定基因型的队列中有效。

World-wide HIV infection rates remain remarkably high despite a thorough understanding of the epidemiological and behavioral risk factors for acquisition. These risk factors are of a diverse nature and include high risk sexual practices, geographical HIV prevalence, virus load in the transmitter, circumcision status and other sexually transmitted infections such as herpes simplex virus type 2 infection. However, the observation that in very similar risk settings only some persons become infected whereas others do not remains somewhat enigmatic. In this project we aim is to used novel precision GWAS approaches to discover host genomic polymorphisms that determine protection from and susceptibility to the acquisition of HIV. We performed a two-stage wholly NGS-based analysis of the high-risk HVTN 505 vaccine cohort as well as carefully matched HIV-infected persons from other cohorts. We used our dataset to explore the separate additional question of host genetic influence on vaccine efficacy in the HVTN 505 trial. We discovered multiple polymorphisms with very high significance that that determine protection from and susceptibility to HIV acquisition. We found that HVTN 505 was efficacious in 30% of the cohort with a specific genotype.