暴露史在 HIV 感染中的作用:来自重复低剂量挑战研究的见解。
The role of exposure history on HIV acquisition: insights from repeated low-dose challenge studies.
机构信息
Integrative Biology, ETH Zurich, Zurich, Switzerland.
出版信息
PLoS Comput Biol. 2012;8(11):e1002767. doi: 10.1371/journal.pcbi.1002767. Epub 2012 Nov 8.
To assess the efficacy of HIV vaccine candidates or preventive treatment, many research groups have started to challenge monkeys repeatedly with low doses of the virus. Such challenge data provide a unique opportunity to assess the importance of exposure history for the acquisition of the infection. I developed stochastic models to analyze previously published challenge data. In the mathematical models, I allowed for variation of the animals' susceptibility to infection across challenge repeats, or across animals. In none of the studies I analyzed, I found evidence for an immunizing effect of non-infecting challenges, and in most studies, there is no evidence for variation in the susceptibilities to the challenges across animals. A notable exception was a challenge experiment by Letvin et al. Sci Translat Med (2011) conducted with the strain SIVsmE660. The challenge data of this experiment showed significant susceptibility variation from animal-to-animal, which is consistent with previously established genetic differences between the involved animals. For the studies which did not show significant immunizing effects and susceptibility differences, I conducted a power analysis and could thus exclude a very strong immunization effect for some of the studies. These findings validate the assumption that non-infecting challenges do not immunize an animal - an assumption that is central in the argument that repeated low-dose challenge experiments increase the statistical power of preclinical HIV vaccine trials. They are also relevant for our understanding of the role of exposure history for HIV acquisition and forecasting the epidemiological spread of HIV.
为了评估 HIV 疫苗候选物或预防疗法的疗效,许多研究小组已经开始用低剂量的病毒反复挑战猴子。这种挑战数据为评估暴露史对感染获得的重要性提供了一个独特的机会。我开发了随机模型来分析之前发表的挑战数据。在数学模型中,我允许动物在多次挑战或不同动物之间的感染易感性存在差异。在我分析的研究中,没有一个研究为非感染性挑战的免疫作用提供了证据,而且在大多数研究中,动物之间对挑战的易感性没有差异的证据。一个值得注意的例外是 Letvin 等人进行的挑战实验。Sci Translat Med(2011)使用 SIVsmE660 株进行。该实验的挑战数据显示出动物间明显的易感性差异,这与涉及动物之间先前建立的遗传差异一致。对于没有显示出显著免疫作用和易感性差异的研究,我进行了功效分析,因此可以排除一些研究中存在非常强的免疫作用。这些发现验证了一个假设,即非感染性挑战不会使动物免疫——这一假设是反复进行低剂量挑战实验增加临床前 HIV 疫苗试验统计功效的核心论点。它们对于我们理解暴露史在 HIV 获得中的作用以及预测 HIV 的流行病学传播也具有重要意义。