Pathogenesis of Clade C HIV Infection

C 分支 HIV 感染的发病机制

• 批准号: 7763243
• 负责人: Bruce D Walker
• 金额: $ 60.25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7763243
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Acute; Address; African; Alleles; Antigens; Attenuated; Automobile Driving; C-Peptide; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Chronic Phase; Collaborations; Containment; Data; Development; Disease; Disease Progression; Epidemic; Epitopes; Evolution; Genetic; Goals; HIV; HIV Infections; HIV vaccine; Human; Immune; Immune response; Immunodominant Epitopes; Immunologic Factors; Immunologics; Infection; Mutation; Pathogenesis; Pathway interactions; Persons; Population; Research; Resolution; Resources; Role; Simian B disease; Solid; South Africa; Southern Africa; T cell response; T-Lymphocyte; Vaccine Design; Vaccines; Viral; Viral Load result; Viremia; Virus; Virus Diseases; Walkers; cohort; design; fitness; follow-up; pandemic disease; pressure; programs; virus host interaction

Empiric approaches to develop an effective AIDS vaccine have not been successful; indeed, the precise goals for a vaccine are unknown as the correlates of protection from infection and disease progression remain to be defined. Moreover, a major obstacle to design of an effective immunogen is the need to target diverse strains of HIV that are encountered worldwide. To address these issues, we have developed a collaborative research program at the center of the South African AIDS epidemic in KwaZulu Natal. This has allowed us to initiate simultaneous examination of viral, host genetic and immunologic factors that modulate acute and chronic HIV infection, and now allows us to expand these studies in large enough cohorts to be able to control for the diverse HLA types encountered in human populations. Such comprehensive and integrated data do not exist currently. Preliminary data already generated from South Africa suggest that the virus-host interaction is highly predictable, both in terms of epitopes targeted and the pathways to immune escape that are tolerated by the virus. With established mechanisms for over 95% successful longitudinal follow up of persons in this cohort, we are poised to define the precise epitopes targeted in acute and chronic infection associated with initial and persistent containment of viremia, and to determine the preferred mutations that arise at immunodominant epitopes targeted in clade C virus infection, which makes up the majority of global cases. Moreover, the proposed studies will allow us to define the adaptive virus-specific CD4 T+ cell response in clade C virus infection, and the role of these cells and the restricting class II alleles in disease pathogenesis. These issues are critical for HIV vaccine design and for understanding HIV pathogenesis. We propose to build on our solid preliminary data and outstanding functional collaborations to 1) Define the CD4+ and CD8+ T cell immune responses in persons with Clade C virus infection that contribute to containment of viremia, focusing on the most prevalent HLA alleles in Southern Africa, and persons with both acute and chronic infection; 2) Define the evolution of clade C HIV under cellular immune selection pressure; 3) Determine the impact of immune selection pressure on viral replicative fitness of clade C HIV infection.

开发有效艾滋病疫苗的经验方法尚未成功。确实，确切的 疫苗的目标是未知的，因为保护与疾病进展的保护相关 仍然有待定义。此外，设计有效免疫原的主要障碍是需要 全世界遇到的各种艾滋病毒菌株。为了解决这些问题，我们已经开发了 南非中心的合作研究计划在夸祖鲁·纳塔尔（Kwazulu Natal）艾滋病流行病。这 使我们能够同时检查病毒，宿主遗传和免疫学因素 调节急性和慢性艾滋病毒感染，现在允许我们扩大足够大的研究 能够控制人口中遇到的不同HLA类型的同伙。这样的 目前不存在全面和集成的数据。已经从南部生成的初步数据 非洲表明，在针对的表位和 通过病毒耐受的免疫逃逸途径。拥有超过95％以上的确定机制 在这个队列中成功的纵向跟进，我们准备定义确切的表位 针对急性和慢性感染，与病毒血症的初始和持续遏制有关 确定针对进化枝C病毒感染的免疫主流表位上出现的首选突变， 构成了大多数全球案件。此外，拟议的研究将使我们能够定义 进化枝C病毒感染中自适应病毒特异性CD4 T+细胞反应，这些细胞的作用和 限制疾病发病机理中II类等位基因。这些问题对于艾滋病毒疫苗设计至关重要 了解HIV发病机理。我们建议以扎实的初步数据和出色的稳定的初步数据为基础 1）在具有进化枝C的人中定义CD4+和CD8+ T细胞免疫反应的功能协作 病毒感染导致病毒血症的控制，重点是最普遍的HLA等位基因 南部非洲，患有急性和慢性感染的人； 2）定义进化枝C艾滋病的演变 在细胞免疫选择压力下； 3）确定免疫选择压力对病毒的影响 进化枝C艾滋病毒感染的复制适应性。