The Biology of HIV Transmission

HIV传播的生物学

基本信息

批准号：
8043728
负责人：
Frederick M Hecht
金额：
$ 39.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8043728
关键词：
Acceleration Acquired Immunodeficiency Syndrome Acute Address Affect Affinity Africa Alleles Anti-Retroviral Agents Area Attention Autologous Automobile Driving Avidity Binding Biological Biological Assay Biology of HIV Transmission Brazil CCR5 gene CD4 Positive T Lymphocytes CD8B1 gene Case Study Cell Count Characteristics Chemokine (C-C Motif) Receptor 5 Clinical Clinical Data Cohort Studies Complex Counseling Cryopreservation Cytotoxic T-Lymphocytes Data Data Quality Data Set Databases Detection Developing Countries Development Disease Disease Progression Doctor of Philosophy Drug resistance Enrollment Ensure Environment Epidemic Epitopes Escape Mutant Evolution Exposure to Failure Frequencies Gagging Genome Genotype Gerda brand of difluprednate Glycoproteins Goals Grant HIV HIV Infections Immune Immune response Immunity Immunologics Immunology Immunophenotyping Individual Infection Integration Host Factors Interdisciplinary Study Knowledge Laboratories Laboratory Markers Lead Leadership Length Ligands Link Location Measures Memory Methods Modeling Monitor Mutation North America Participant Pathogenesis Peptides Persons Pharmaceutical Preparations Phenotype Phylogenetic Analysis Plasma Predisposition Process Property RNA Recruitment Activity Reporting Research Research Infrastructure Research Personnel Research Project Grants Resistance Resources Risk Role SIV San Francisco Scientist Secondary Prevention Serum Shapes Site Source Specimen Specimen Handling Statistical Methods Structure T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Epitopes Testing Time Tropism Universities Ursidae Family Vaccine Design Vaccines Variant Viral Viral Load result Viral Vector Viremia Virulent Virus Work antiretroviral therapy base cell mediated immune response chemokine cohort cost data integration data management experience fitness follow-up genetic evolution glycosylation high risk inhibitor/antagonist innovation insight interest medical schools meetings multidisciplinary neutralizing antibody nonhuman primate organizational structure preference pressure programs quality assurance receptor receptor binding resistance mutation response sound superinfection transmission process vector virology

项目摘要

This program project application brings together a strong multidisciplinary team to study key issues in the virology and immunology of HIV transmission, early pathogenesis, and superinfection during early HIV. The Clinical Core will provide a central resource for the proposed projects by recruiting and following persons with acute and early HIV. A unique resource will be enrollment of potential source partners who transmitted HIV. The Clinical Core will be based on an acute/early HIV program that has a strong track record of recruiting persons with acute/early HIV as well as identifying their source partners. In addition to recruitment in the San Francisco area, a second Clinical Core site in southern Brazil will provide additional acute/early infection cases and transmission pairs in an area with a nearly 50/50 mix of subtype B and C HIV, allowing comparisons between HIV subtypes. Four closely integrated studies are planned: Project 1 (Hecht PI) will examine the transmission of cytotoxic T-lymphocyte (CTL) escape and drug resistance mutations and their persistence after transmission. It will test the hypotheses that there are not substantial barriers to transmission of drug resistant and CTL escape variants present in source partners, and that differences in viral fitness will predict time to emergence of wild type virus in persons with primary drug resistance or CTL escape mutations. Project 2 (Deeks PI) will examine the role of HIV env properties, in particular co-receptor utilization, during transmission from source to spread partner and evolution following transmission. It will test the role of CCR5 related viral properties, such as receptor binding avidity, in viral transmissibility. It will also investigate the relationship between host CCR5 receptor and ligand genetics and evolution of viral coreceptor properties following HIV transmission. Project 3 (Grant PI) will prospectively follow participants over the first years following HIV infection to better determine the risk of superinfection by time since infection and virologic and humoral immune predictors of susceptibility to superinfection. Project 4 (Nixon PI) will examine the role of HIV specific T-cell responses in driving reversion of CTL escape mutations acquired during HIV transmission to a partner with a different HLA type and the role of CTL responses in superinfection. The Administrative and Analysis Core will provide scientific leadership and data management and statistical support. The overarching aims of this proposal are to advance our understanding of the immunologic and virologic factors that reduce the vulnerability of individuals to superinfection in the first 2-3 years of infection, and to better understand the evolution of HIV as it adapts to a new host environment following transmission. This will provide critical insights into the development of protective immunity following HIV infection, and into the evolution and pathogenesis of HIV in early infection.

该计划项目申请汇集了强大的多学科团队，研究艾滋病毒传播的病毒学和免疫学、早期发病机制以及早期艾滋病毒期间的重复感染等关键问题。临床核心将通过招募和跟踪急性和早期艾滋病毒感染者，为拟议项目提供核心资源。一个独特的资源将是招募传播艾滋病毒的潜在来源伙伴。临床核心将基于急性/早期艾滋病毒项目，该项目在招募急性/早期艾滋病毒患者以及确定其来源伙伴方面拥有良好的记录。此外在旧金山地区的招募中，巴西南部的第二个临床核心站点将在 B 型和 C 型 HIV 混合比例接近 50/50 的地区提供更多急性/早期感染病例和传播对，从而可以对 HIV 亚型进行比较。计划进行四项紧密结合的研究：项目 1 (Hecht PI) 将检查细胞毒性 T 淋巴细胞 (CTL) 逃逸和耐药突变的传播及其在传播后的持续性。它将检验以下假设：源伙伴中存在的耐药性和 CTL 逃逸变体的传播不存在实质性障碍，并且病毒适应性的差异将预测主要药物人群中野生型病毒出现的时间耐药性或 CTL 逃逸突变。项目 2（Deeks PI）将研究 HIV 环境特性的作用，特别是辅助受体的利用，在从源头传播到传播伙伴的过程中以及传播后的进化过程中。它将测试 CCR5 相关病毒特性（例如受体结合亲和力）在病毒传播中的作用。它还将研究宿主 CCR5 受体和配体遗传学之间的关系以及 HIV 传播后病毒辅助受体特性的进化。项目 3（Grant PI）将在 HIV 感染后的头几年对参与者进行前瞻性跟踪，以便根据感染后的时间以及对重复感染易感性的病毒学和体液免疫预测因子更好地确定重复感染的风险。项目 4（Nixon PI）将研究 HIV 特异性 T 细胞反应在驱动 HIV 传播给具有不同 HLA 类型的伴侣期间获得的 CTL 逃逸突变的逆转中的作用，以及 CTL 反应在重复感染中的作用。行政和分析核心将提供科学领导、数据管理和统计支持。该提案的总体目标是增进我们对免疫学和病毒学因素的理解，这些因素可降低个体在感染后 2-3 年内发生重复感染的可能性，并更好地了解 HIV 在适应新宿主时的演变传输后的环境。这将为了解艾滋病毒感染后保护性免疫的发展以及早期感染艾滋病毒的演变和发病机制提供重要见解。