Constraints on HIV-1 Diversity from Protein Structure
Constraints on HIV-1 Diversity from Protein Structure
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DOI：
10.1128/jvi.00702-10
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发表时间：
2010-12-01
影响因子：
5.4
通讯作者：
Lovell, Simon C.
中科院分区：
文献类型：
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作者：
Woo, Jeongmin;Robertson, David L.;Lovell, Simon C.
HIV-1的高进化速度有助于免疫逃逸，使病毒能够逃脱药物治疗，并可能成为生产有效疫苗的困难的基础。因此，确定艾滋病毒演变的制约因素至关重要。为了研究这个问题，我们研究了序列多样性、选择和蛋白质结构之间的关系。我们发现，虽然序列多样性随着时间的推移而增加，但这种变异有限制在特定结构区域的趋势。相反，当分析单个位点时，对Gag和env有大量和广泛的进化限制。即使在高度可变的包膜蛋白中也存在这种限制。个体站点的进化意义由选择压力沿时间进程的变化来表示：增加熵表明该站点主要以更像时钟的方式进化，不增加的低熵值表示高度约束，而高熵值表示缺乏约束。很少有网站表现出高成交率。将这些位置映射到三维蛋白质结构上，我们发现埋藏在蛋白质核心和表面的区域的进化速度有显著差异。这种限制在所分析的时间段内不会改变，也不依赖于亚型，因为在B和C亚型中发现了类似的结果。这种序列和结构之间的联系不仅表明了最近HIV-1进化的局限性，也强调了进化限制病毒变化的起源。
The high rate of HIV-1 evolution contributes to immune escape, enables the virus to escape drug therapy, and may underlie the difficulty of producing an effective vaccine. Identifying constraints on HIV evolution is therefore of prime importance. To investigate this problem, we examined the relationships between sequence diversity, selection, and protein structure. We found that while there was an increase in sequence diversity over time, this variation had a tendency to be limited to specific structural regions. When individual sites were analyzed, there was, in contrast, substantial and widespread evolutionary constraint over gag and env. This constraint was present even in the highly variable envelope proteins. The evolutionary significance of an individual site is indicated by the change in selection pressure along the time course: increasing entropy indicates that the site is evolving predominantly in a more "clock"-like manner, low entropy values with no increase indicate a high degree of constraint, and high entropy values indicate a lack of constraint. Few sites display high degrees of turnover. Mapping these sites onto the three-dimensional protein structure, we found a significant difference between evolutionary rates for regions buried in the core of the protein and those on the surface. This constraint did not change over the time period analyzed and was not subtype dependent, as similar results were found for subtypes B and C. This link between sequence and structure not only demonstrates the limits of recent HIV-1 evolution but also highlights the origins of evolutionary constraint on viral change.