Impact of CCR5delta32 Host Genetic Background and Disease Progression on HIV-1 Intrahost Evolutionary Processes: Efficient Hypothesis Testing through Hierarchical Phylogenetic Models
Impact of CCR5delta32 Host Genetic Background and Disease Progression on HIV-1 Intrahost Evolutionary Processes: Efficient Hypothesis Testing through Hierarchical Phylogenetic Models
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DOI：
10.1093/molbev/msq326
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发表时间：
2011-05-01
影响因子：
10.7
通讯作者：
Suchard, Marc A.
中科院分区：
文献类型：
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作者：
Edo-Matas, Diana;Lemey, Philippe;Suchard, Marc A.
C-C趋化因子受体5型（CCR 5）宿主遗传背景、疾病进展和宿主内HIV-1进化动力学之间的相互作用仍不清楚，因为宿主之间病毒进化的差异限制了在分层为临床相关人群的宿主中得出结论的能力。类似的推断问题在许多可测量的进化病原体中扩散，这些病原体的宿主内序列样品很容易获得。为此，我们提出了新的层次系统发育模型（HPMs），采用随机搜索变量选择和模型平均的正式统计框架中，将固定效应测试的动态差异在主机种群。为了阐明CCR 5宿主遗传背景和疾病进展对病毒进化模式的作用，我们从HIV-1感染人群中的HIV-1变异体中获得了gp 120包膜序列，这些HIV-1变异体在感染过程中的多个时间点分离，这些HIV-1感染人群在所有时间点都只携带CCR 5-使用HIV-1变异体。在双向设计中，存在或不存在CCR 5 wt/delta 32基因型以及进行性或长期非进行性感染过程对临床人群进行分层。与独立分析每个患者的序列的标准方法相比，HPM提供了更有效的进化参数估计，如核苷酸取代率和d（N）/d（S）比率，如估计方差的显著收缩所示。固定效应还校正了人群之间数据的非独立性，并导致个体患者估计值进一步缩小。模型选择表明核苷酸取代率和疾病进展之间的关联，但CCR 5基因型的作用仍然难以捉摸。由于患者组之间没有明显的d（N）/d（S）差异，艾滋病症状的延迟发作似乎仅与较低的病毒复制率有关，而不是与氨基酸固定的选择差异有关。
The interplay between C-C chemokine receptor type 5 (CCR5) host genetic background, disease progression, and intrahost HIV-1 evolutionary dynamics remains unclear because differences in viral evolution between hosts limit the ability to draw conclusions across hosts stratified into clinically relevant populations. Similar inference problems are proliferating across many measurably evolving pathogens for which intrahost sequence samples are readily available. To this end, we propose novel hierarchical phylogenetic models (HPMs) that incorporate fixed effects to test for differences in dynamics across host populations in a formal statistical framework employing stochastic search variable selection and model averaging. To clarify the role of CCR5 host genetic background and disease progression on viral evolutionary patterns, we obtain gp120 envelope sequences from clonal HIV-1 variants isolated at multiple time points in the course of infection from populations of HIV-1-infected individuals who only harbored CCR5-using HIV-1 variants at all time points. Presence or absence of a CCR5 wt/delta 32 genotype and progressive or long-term nonprogressive course of infection stratify the clinical populations in a two-way design. As compared with the standard approach of analyzing sequences from each patient independently, the HPM provides more efficient estimation of evolutionary parameters such as nucleotide substitution rates and d(N)/d(S) rate ratios, as shown by significant shrinkage of the estimator variance. The fixed effects also correct for nonindependence of data between populations and results in even further shrinkage of individual patient estimates. Model selection suggests an association between nucleotide substitution rate and disease progression, but a role for CCR5 genotype remains elusive. Given the absence of clear d(N)/d(S) differences between patient groups, delayed onset of AIDS symptoms appears to be solely associated with lower viral replication rates rather than with differences in selection on amino acid fixation.