Impact of HIV-1 Fitness on Disease Progression

HIV-1 健康状况对疾病进展的影响

基本信息

批准号：
7484266
负责人：
ERIC J ARTS
金额：
$ 37.89万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7484266
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

项目摘要

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健身是由病毒对给定环境的适应性定义的复杂参数。在过去的四年中，我们研究了HIV-1在各种原发性人类细胞中的体内适应性，并探索了与疾病进展以及人类流行病中病毒的全球和时间演变的可能关系。在此提案中，我们将重点关注疾病自然史上复制性HIV-1适应性的变化，并在亚型A，C和D受感染患者中的离散传播事件之后。在过去的三年中，我们分析了来自266名津巴布韦和乌干达妇女在急性感染后三个月内招募的样本，此后每三个月遵循每三个月的进展。该队列还提供了一个极好的机会，可以比较HIV-1亚型对感染和随后的疾病结局的影响。作为这项研究的导致，我们已经发表了相当详尽的比较，就艾滋病毒类型（1或2），组（M和O），亚型（A至F）和重组形式的适应性进行了相当详尽的比较，并发现了Exvivo HIV复制性的顺序：亚型C> HIV-2“ HIV-1组O。基于初步数据，该数据显示了亚型C感染的疾病进展较慢，并且亚型病毒在本质上的适合度较低，我们的研究将解决这两个观察结果，如果这两个观察结果是连接的，如果亚型C代表了衰减的HIV-1形式，则这些假设会构成以下特定的特定目标。产生嵌合Env病毒。将更改与亚型相关联。