Hepatitis C Recombination Incidence and Prevalence

描述(申请人提供)：本R21申请的目的是研究丙型肝炎病毒重组，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，但现在被认为是基因多样化的一种主要方式，代表了免疫逃避和耐药的重要机制。最近，在俄罗斯圣彼得堡的标本中首次报道了丙型肝炎病毒重组的证据。到目前为止，还没有其他重组丙型肝炎病毒基因组的描述。由于大多数对丙型肝炎病毒基因序列的研究都涉及小片段扩增，而重组株的鉴定需要检查多个基因组区域，因此我们假设丙型肝炎病毒重组是一种比目前所认识到的更常见的现象，并对其频率和特征进行了初步研究。我们已经组装了一个大型标本储存库，通过对E1基因的序列分析确定了其基因型。这些标本是从美国4个以1、2和3型为主的城市以及以1、3和6型为主的泰国的感染者身上获得的。我们还描述了包含两个不同的丙型肝炎病毒种群的混合感染的初步调查，这表明存在重组。基于多年来对埃及HIV-1重组、丙型肝炎病毒序列变异和不同丙型肝炎病毒亚型的遗传流行病学研究的经验，我们建议检查我们的资料库，以寻找丙型肝炎病毒重组的证据。这项应用的目标是确定基因重组丙型肝炎病毒是否流行，并对重组基因组进行详细分析。具体地说，我们的目标是：(1)识别在不同的丙型肝炎病毒基因座上存在不一致基因的样本，(2)检查包含多个菌株的样本以检测发生的重组，以及(3)详细描述假定的重组基因组。我们的资料库包括具有良好特性的纵向获取的标本，我们正在应用我们已经建立的专业知识的方法；因此，这项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.