The Biology of HIV Transmission

HIV传播的生物学

• 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
• 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

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.

该计划项目应用程序汇集了一个强大的多学科团队，以研究艾滋病毒早期艾滋病毒传播，早期发病机理和超级感染的病毒学和免疫学上的关键问题。 临床核心将通过招募和追随急性和早期艾滋病毒的人为拟议项目提供中心资源。独特的资源将是传播艾滋病毒的潜在来源合作伙伴的招生。临床核心将基于一个急性/早期艾滋病毒计划，该计划具有急性/早期艾滋病毒的招募人员以及确定其来源伴侣的良好记录。此外 巴西南部的第二个临床核心地点在旧金山地区的招募将提供额外的急性/早期感染病例和传输对，并在接近50/50的亚型B和C HIV中混合了近50/50，从而可以在HIV亚型之间进行比较。计划了四项紧密综合的研究：项目1（Hecht PI）将检查细胞毒性T淋巴细胞（CTL）逃生和耐药性突变的传播及其在传播后的持久性。它将检验以下假设：源伴侣中存在的耐药性和CTL逃生变体的传播没有实质性障碍，并且病毒适应性的差异将预测在原发性药物患者中出现野生型病毒的时间 电阻或CTL逃脱突变。项目2（DEEKS PI）将检查HIV ENV属性的作用，特别是受体利用，在传播后从源到传播伙伴的传播和传播后进化。它将测试CCR5相关的病毒特性的作用，例如受体结合亲和力，在病毒传递性中。它还将研究HIV传播后的宿主CCR5受体与配体遗传学与病毒croector特性的演变之间的关系。项目3（Grant PI）将在HIV感染后的头几年前瞻性地跟随参与者，以更好地确定自感染以及病毒学和体液免疫预测因素对超级感染的易感性以来的超级感染的风险。 项目4（尼克松PI）将研究HIV特异性T细胞响应在将HIV传播期间获得的CTL逃生突变重新转移到具有不同HLA类型的合作伙伴以及CTL响应在超级感染中的作用的作用。行政和分析核心将提供科学领导力和数据管理以及统计支持。该提案的总体目的是促进我们对免疫和病毒学因素的理解，这些因素减少了在感染的头2 - 3年中个人对超级感染的脆弱性，并更好地理解HIV在传播后适应新宿主环境时的艾滋病毒的演变。这将为艾滋病毒感染后的保护性免疫发展以及早期感染中HIV的进化和发病机理提供关键的见解。