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，或交换导致杂交基因组的遗传物质。对于HIV-1，直到1994年，重组还不为人所知，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，在俄罗斯圣彼得堡的标本中报告了丙型肝炎病毒重组的第一个证据。迄今为止，没有其他重组HCV基因组被描述。由于大多数HCV基因序列的研究涉及小扩增子，而重组菌株的鉴定需要检查多个基因组区域，我们假设HCV重组是一种比目前所认识的更普遍的现象，并建议对其频率和特征进行初步研究。我们收集了大量的标本，通过对E1基因的序列分析确定了它们的基因型。这些标本是从基因型1、2和3为主的4个美国城市以及基因型1、3和6为主的泰国的感染者中获得的。我们还描述了混合感染的初步调查，其中包含两种不同的HCV人群，这表明存在重组。基于多年来在埃及调查HIV-1重组、HCV序列变异和各种HCV亚型遗传流行病学的经验，我们建议检查我们的存储库，寻找HCV重组的证据。该应用程序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。具体来说，我们的目标是：(1)在不同的HCV基因座上鉴定不一致的基因型标本，(2)检查含有多个菌株的标本以检测事件重组，(3)详细表征推定的重组基因组。我们的储存库包括具有良好特征的纵向获得的标本，我们正在应用我们已经建立的专业知识的方法；因此，此应用程序成功的可能性很高。由于丙型肝炎病毒重组的影响尚未确定，R21资助将提供充分的初步数据，以确定更广泛调查的重要性和适当进行。

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.