Hepatitis C Recombination Incidence and Prevalence

描述（由申请人提供）：本R21申请的目的是研究HCV重组，或导致杂交基因组的遗传物质交换。对于HIV-1，重组直到1994年才被发现，但现在被认为是遗传多样化的主要模式，代表了免疫逃避和耐药性的重要机制。最近，在俄罗斯彼得堡的标本中报道了HCV重组的第一个证据。迄今为止，还没有其他重组HCV基因组被描述。由于大多数研究的HCV基因序列涉及小的扩增子，而重组株的鉴定需要检查多个基因组区域，我们假设，HCV重组是一个更常见的现象比目前认识到，并提出初步研究其频率和字符。我们已经组装了一个大型的标本库，通过E1基因的序列分析确定了这些标本的基因型。这些标本来自美国4个城市的感染者，其中基因型1，2和3占主导地位，以及泰国，其中基因型1，3和6占主导地位。我们还描述了混合感染的初步调查，包含两个不同的人群的HCV，这表明存在重组。建立在多年的经验调查HIV-1重组，HCV序列变异，在埃及不同的HCV亚型的遗传流行病学，我们建议检查我们的库中的证据重组HCV。本申请的目的是确定基因重组HCV是否普遍存在，并对重组基因组进行详细分析。具体而言，我们的目标是：（1）鉴定在不同HCV基因座上具有不一致基因型的标本，（2）检查含有一种以上毒株的标本，以检测偶发重组，（3）详细描述推定重组基因组。我们的储存库包括特征良好的纵向采集标本，并且我们正在应用我们已建立专业知识的方法;因此，该应用成功的可能性很高。由于丙型肝炎病毒重组的影响尚未确定，R21基金将提供足够的初步数据，以确定更广泛调查的重要性和适当的进行。

DESCRIPTION (provided by applicant): The purpose of this R21 application is to study HCV recombination, or the exchange of genetic material resulting in hybrid genomes. For HIV-1, recombination was obscure until 1994 but is now recognized as a major mode of genetic diversification, representing an important mechanism for immune evasion and drug resistance. Recently, the first evidence of recombination in HCV was reported in specimens from St. Petersburg, Russia. To date, no other recombinant HCV genomes have been described. Because most studies of HCV genetic sequence have involved small amplicons, whereas identification of a recombinant strain requires examination of multiple genomic regions, we hypothesize that HCV recombination is a more common phenomenon than currently appreciated, and propose initial studies of its frequency and character. We have assembled a large repository of specimens for which genotype has been determined at by sequence analysis of the E1 gene. These specimens have been obtained from infected individuals in 4 U.S. cities where genotypes 1, 2, and 3 predominate, as well as Thailand where genotypes 1, 3, and 6 predominate. We also describe initial investigations of a mixed infection, containing two distinct populations of HCV, which suggest the presence of recombination. Building on years of experience investigating HIV-1 recombination, HCV sequence variation, and the genetic epidemiology of diverse HCV subtypes in Egypt, we propose to examine our repository for evidence of recombination in HCV. The goal of this application is to determine whether genetic recombinant HCV is prevalent, and to performed detailed analysis of recombinant genomes. Specifically, we aim to: (1) identify specimens with discordant genotypes at separate HCV loci, (2) examine specimens containing more than one strain to detect incident recombination, and (3) characterize putative recombinant genomes in detail. Our repository includes well-characterized longitudinally- acquired specimens and we are applying methods for which we have established expertise; therefore, this application has a high likelihood of success. Because the impact of HCV recombination has not yet been determined, R21 funding will provide adequate preliminary data to establish the importance and proper conduct of more extensive investigations.