The HIV-1 and HCV Transmission Bottleneck in Chinese Injection Drug Users

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)和人类免疫缺陷病毒1型(HIV-1)在注射吸毒者(IDU)中传播的病毒种群瓶颈仍然是一个研究不足和有争议的研究领域，与预防工作(包括疫苗设计和评估)具有很大的潜在相关性。单基因组测序(SGS)代表了一种强大的策略，用于识别和表征负责建立生产性临床感染的病毒(称为传播/创立者，或T/F， 病毒)。科学家最近才开始将这种方法应用于注射吸毒者中艾滋病毒和丙型肝炎病毒的传播；只有两项小型研究列举了注射吸毒者中的HIV-1 T/F病毒，结论相互矛盾，还有一项关于丙型肝炎病毒在血浆捐献者中传播的研究，从技术上讲，注射吸毒者被排除在外。重要的是，这些HIV-1和丙型肝炎病毒队列既没有纵向样本，也没有全面的行为数据，这对静脉注射吸毒者区分性传播和注射相关病毒感染至关重要。在这项应用中，我们建议将对导致生产性临床感染的艾滋病毒-1和丙型肝炎病毒T/F病毒的新的定量和定性分析与对注射和性传播危险行为的详细评估相结合，该研究人群包括新疆最近两项艾滋病毒预防试验单位研究的52例HIV-1血清转换和71例丙型肝炎血清转换。这项应用测试了IDU传播由可量化的行为风险控制的假设，这些风险决定了病毒获得率、病毒感染的多样性、病毒表型以及艾滋病毒和丙型肝炎病毒感染的临床结果。我们将通过(I)从新疆HIV-1和丙型肝炎病毒感染者中鉴定和列举T/F HIV-1和丙型肝炎病毒，(Ii)推断传播方式(性传播和注射传播)，并确定HIV-1和丙型肝炎病毒感染和多重病毒传播的行为相关性，(Iii)评估病毒感染的多样性对艾滋病毒和丙型肝炎临床结局的作用，以及(Iv)分子克隆和确定T/F HIV-1 env的生物学表型和来自中国注射吸毒者队列的丙型肝炎病毒全长基因组的复制能力。准确描述注射吸毒者中艾滋病毒和丙型肝炎病毒的传播瓶颈及其在临床疾病进展中的作用将提供与艾滋病毒-1和丙型肝炎病毒传播、自然病史和预防相关的关键信息，此外，还将为针对中国、东南亚和中亚地区的艾滋病毒-1和丙型肝炎病毒株的疫苗研究提供必要的病毒学数据和分子试剂。

DESCRIPTION (provided by applicant): The virus population bottleneck to Hepatitis C Virus (HCV) and Human Immunodeficiency Virus type 1 (HIV-1) transmission in injection drug users (IDUs) remains an understudied and controversial area of research with substantial potential relevance to prevention efforts, including vaccine design and assessment. Single genome sequencing (SGS) represents a powerful strategy for identifying and characterizing viruses that are responsible for establishing productive clinical infection (termed transmitted/founder, or T/F, viruses). Scientists have only recently begun to apply this approach to HIV and HCV transmission in IDUs; there are just two small studies enumerating HIV-1 T/F viruses in IDU subjects with conflicting conclusions, and a single study of HCV transmission in plasma donors where IDU were technically excluded. Importantly, these HIV-1 and HCV cohorts had neither longitudinal sampling nor comprehensive behavioral data available, which are critical in IDUs to distinguish between sexual and injection-related virus acquisition. In this application, we propose to combine novel quantitative and qualitative analyses of the HIV-1 and HCV T/F viruses responsible for productive clinical infection with a detailed assessment of injection and sexual transmission risk behaviors in a robust and clinically well-defined study population of 52 HIV-1 seroconversions and 71 HCV seroconversions from two recent HIV Prevention Trials Unit studies in Xinjiang, China. This application tests the hypothesis that IDU transmission is governed by quantifiable behavioral risks that determine the rates of virus acquisition, the multiplicity of virus infection, the virus phenotype and clinical outcomes of HIV and HCV infection. We will address this hypothesis by (i) identifying and enumerating the T/F HIV-1 and HCV viruses from the Xinjiang IDUs with acute HIV-1 and HCV infection, (ii) inferring the mode of transmission (sexual vs. injection) and determining the behavioral correlates of HIV-1 and HCV acquisition and multiple virus transmission, (iii) assessing the role of multiplicity of virus infection on HIV and HCV clinical outcomes, and (iv) molecularly cloning and determining the biologic phenotype of T/F HIV-1 Envs and the replication competence of HCV full-length genomes from this cohort of Chinese IDUs. Accurate characterization of the HIV and HCV transmission bottleneck in IDUs and its role in clinical disease progression will provide key information relevant to HIV-1 and HCV transmission, natural history and prevention, and in addition, will provide essential virologic data and molecular reagents for vaccine research focused on HIV-1 and HCV strains relevant to China, Southeast and Central Asia.