Impact of HIV-1 Fitness on Disease Progression

HIV-1 健康状况对疾病进展的影响

• 批准号: 7340958
• 负责人: ERIC J ARTS
• 金额: $ 38.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340958
• 关键词: Acute; Address; Affect; Anti-Retroviral Agents; Appendix; Applications Grants; Attenuated; Back; Bayesian Method; Belgium; Biostatistics Core; Blood; Bulla; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Cervical; Clinic; Clinical; Clinical Chemistry Tests; Clinical Research; Cloning; Code; Collaborations; Complex; Consult; Contracts; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Disease Outcome; Disease Progression; Drops; End Point; Environment; Epidemic; Event; Evolution; Family health status; Founder Effect; Future; Genes; Genetic; Genetic Variation; Genome; HIV; HIV-1; HIV-2; Human; Immune; Immune response; Individual; Infection; Institutes; International; Lamina Propria; Lead; Length; Link; London; Long-Term Survivors; Malaria; Maps; Measures; Methods; Modeling; Mucous Membrane; Mutation; National Institute of Child Health and Human Development; Natural History; Opportunistic Infections; Oregon; Other Genetics; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Process; Program Research Project Grants; Proteins; Publishing; Questionnaires; Quinones; Rate; Recombinants; Recording of previous events; Recruitment Activity; Relative (related person); Research; Research Design; Resistance; Sampling; Science; Screening procedure; Services; Sexual Transmission; Skin; Source; Stress; System; T-Lymphocyte; Techniques; Testing; Time; Tropical Medicine; Uganda; Universities; University Hospitals; Vagina; Vertebral column; Viral; Viral Load result; Virulence; Virulent; Virus; Visit; Washington; Woman; Yeasts; Zimbabwe; attenuation; base; benzoquinone; cohort; college; disease natural history; env Genes; fitness; follow-up; genetic analysis; in vivo; macrophage; mathematical model; oral infection; pandemic disease; physical separation; pressure; symposium; trait; transmission process

DESCRIPTION (provided by applicant): HIV-1 fitness is a complex parameter defined by the adaptability of the virus to a given environment. Over the past four years we have studied the ex vivo fitness of HIV-1 in various primary human cells and have explored possible relationships with disease progression as well as global and temporal evolution of the virus in the human epidemic. In this proposal we will focus on changes in replicative HIV-1 fitness during the natural history of disease and following discrete transmission events in subtype A, C, and D infected patients. Over the past three years, we have analyzed samples from over 266 Zimbabwean and Ugandan women recruited within three months of acute infections and have followed their progression every three months thereafter. This cohort also provides an excellent opportunity to compare the affects of HIV-1 subtype on infection and subsequent disease outcomes. As a lead up to this study, we have published fairly exhaustive comparisons on the fitness of HIV types (1 or 2), groups (M and O), subtype (A through F), and recombinant forms and found the order of ex vivo HIV replicative fitness to be: HIV-1 group M (subtypes A, B, D, F, CRF01_AE, CRF02_AG, CRF012_BF) > subtype C > HIV-2 " HIV-1 group O. Based on preliminary data that shows slower disease progression in subtype C infections and that subtype C virus is intrinsically less fit, our study will address if these two observations are linked and if subtype C represents an attenuated HIV-1 form. These hypotheses will be tested in the following specific aims. Specific aim 1: To establish a rapid yeast-based env cloning system to produce chimeric env viruses. To further examine if ex vivo HIV-1 fitness maps to the env gene and is controlled by the HIV-1 entry process into host cells. Specific aim 2: To explore the relationships between HIV-1 fitness/diversity at acute/early infection Specific aim 3: To examine changes in viral fitness, genetic diversity, and other clinical correlates during disease progression. To relate changes to subtype.

描述（由申请人提供）：HIV-1 适应性是一个复杂的参数，由病毒对给定环境的适应性定义。在过去的四年里，我们研究了 HIV-1 在各种原代人类细胞中的离体适应性，并探索了与疾病进展以及人类流行病中病毒的整体和时间进化的可能关系。在本提案中，我们将重点关注 A、C 和 D 亚型感染患者在疾病自然史期间以及离散传播事件后 HIV-1 复制适应性的变化。在过去的三年里，我们分析了超过 266 名津巴布韦和乌干达妇女的样本，这些妇女是在三个月内招募的急性感染患者，并在此后每三个月跟踪一次她们的进展情况。该队列还提供了一个绝佳的机会来比较 HIV-1 亚型对感染和随后疾病结果的影响。作为这项研究的准备，我们发表了对 HIV 类型（1 或 2）、组（M 和 O）、亚型（A 至 F）和重组形式的适应性的相当详尽的比较，并发现离体 HIV 复制适应性的顺序为：HIV-1 M 组（亚型 A、B、D、F、CRF01_AE、CRF02_AG、CRF012_BF）> C亚型> HIV-2“HIV-1 O组。根据显示C亚型感染疾病进展较慢且C亚型病毒本质上不太适合的初步数据，我们的研究将解决这两个观察结果是否相关以及C亚型是否代表HIV-1减毒形式。这些假设将在以下具体目标中进行测试。具体目标1：建立基于酵母的快速环境克隆系统 产生嵌合环境病毒。进一步检查离体 HIV-1 适应性是否映射到 env 基因并受 HIV-1 进入宿主细胞的过程控制。具体目标 2：探讨急性/早期感染时 HIV-1 适应性/多样性之间的关系 具体目标 3：检查疾病进展期间病毒适应性、遗传多样性和其他临床相关性的变化。将更改与子类型相关联。