Molecular Archeology of HIV

描述(申请人提供)：由于像HIV-1这样的逆转录病毒进化如此之快，从出现之前的短短几十年中检索到的病毒基因序列实际上是分子“化石”。这样的化石序列可以用来提供在早期时间点特定微生物存在的无可争辩的证据，验证原本无法测试的历史推断，并提供对艾滋病大流行当前演变和动态的洞察。它们照亮了原本会丢失的遥远过去的部分，并可以提供手段来测试关于医学上重要病毒的起源、发病机制、适应、传播、持久性和传播动力学的重要假说。控制艾滋病毒的战斗需要尽可能最好地了解其目前的遗传多样性，而这种了解最好可以通过在历史遗传变异的背景下查看当代基因序列来实现。除了为数不多的几个例外，对于艾滋病毒-1 M组，这一提议的焦点，迄今为止还没有利用分子考古学的观点。该项目的总体目标是通过恢复和分析从过去收集的信息，全面和综合地努力了解艾滋病毒-1 M组的未来。为了实现这一目标，我们的目标是：1.使用20世纪70年代的档案标本，揭示艾滋病毒-1在北美的起源和出现的历史；2.从1960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的包膜基因和基因组序列；3.调查中部非洲M组艾滋病毒-1的早期遗传多样性，以及它如何通过筛选大量艾滋病毒-1档案样本并对所得数据集进行序列和系统发育分析来了解这一重要地区目前的遗传多样性。至关重要的是，我们收集了大量的档案标本，其中许多来自艾滋病毒研究领域尚未被广泛考虑的来源，我们将用这些标本来阐明艾滋病毒进化的显著未被研究的早期阶段(大约从发现艾滋病的时间，回到20世纪60年代，甚至更早)直到今天。我们的专业知识和过往记录使我们处于进行这项重要研究的独特地位。

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.