Molecular Archeology of HIV

描述（由申请人提供）：因为像HIV-1这样的逆转录病毒进化得如此之快，从几十年前检索到的病毒基因序列实际上是分子“化石”。这种化石序列可用于提供无可争辩的证据，证明某一特定微生物在一个早期时间点存在，验证否则无法检验的历史推论，并提供对艾滋病流行的当前演变和动态的深入了解。它们照亮了原本可能被遗忘的那部分深刻的过去，并提供了检验关于医学上重要病毒的起源、发病机制、适应、传播、持续和传播动力学的重要假设的手段。控制艾滋病毒的斗争需要对其当前的遗传多样性有最好的了解，而这种了解可以通过在历史遗传变异的背景下观察当代基因序列来实现。除了少数例外，“分子考古学”的观点迄今为止还没有被用于研究HIV-1 M组，这是本提案的重点。该项目的总体目标是通过恢复和分析从过去收集的信息，做出全面和综合的努力，了解HIV-1 M组的未来。为实现这一目标，我们的目标是1。利用20世纪70年代的档案标本，揭示HIV-1在北美的起源和出现的历史；2. 从20世纪60年代或更早的多个石蜡包埋组织样本中恢复和分析近全长包膜基因，如果可能的话，恢复和分析HIV-1基因组序列；3. 通过筛选大量HIV-1档案样本并对结果数据集进行序列和系统发育分析，调查中非HIV-1 M组的早期遗传多样性，以及它如何为了解这一重要地区当前的遗传多样性提供信息。至关重要的是，我们收集了大量的档案标本，其中许多标本的来源尚未在艾滋病毒研究领域得到广泛考虑，我们将利用这些标本阐明艾滋病毒进化的早期阶段（从发现艾滋病的时候开始，追溯到20世纪60年代甚至更早），直到今天。我们的专业知识和业绩记录使我们在开展这项重要研究方面处于独特的地位。

DESCRIPTION (provided by applicant): Because retroviruses like HIV-1 evolve so rapidly, viral genetic sequences retrieved from just a few decades before present are effectively molecular 'fossils'. Such fossil sequences can be used to provide indisputable evidence of the existence of a given microbe at an early time point, to validate historical inferences that could otherwise not be tested, and to provide insight into the current evolution and dynamics of the AIDS pandemic. They light up portions of the deep past that would otherwise be lost, and can provide the means to test important hypotheses about the origins, pathogenesis, adaptation, spread, persistence, and transmission dynamics of medically important viruses. The battle to control HIV requires the best possible understanding of its current genetic diversity, and such understanding can best be achieved by viewing contemporary gene sequences in the context of historical genetic variation. With just a handful of exceptions, the 'molecular archeology' perspective has to date not been exploited with respect to HIV-1 group M, the focus of this proposal. The overarching aim of this project is to make a comprehensive and integrated effort to understand the future of HIV-1 group M by recovering then analyzing information gleaned from its past. To accomplish this we will aim 1. to use archival specimens from the 1970s to uncover the history of the origin and emergence of HIV-1 in North America; 2. to recover and analyze near- full-length envelope gene and, if possible, genomic HIV-1 sequence from multiple paraffin- embedded tissue samples from the 1960 and perhaps earlier; 3. to investigate the early genetic diversity of HIV-1 group M in central Africa and how it informs understanding of the current genetic diversity in this important region by screening large numbers of archival samples for HIV-1 and conducting sequence and phylogenetic analyses on the resulting data set. Crucially, we have assembled a massive collection of archival specimens, many from sources that have not yet been widely considered in the field of HIV research, with which we will illuminate the remarkably unstudied early phase of HIV evolution (from around the time of the discovery of AIDS, back to 1960s and perhaps even earlier) right up to the present day. Our expertise and track record make us uniquely positioned to conduct this important research.