Mechanistic Studies of HIV-exposed Seronegative Individuals

HIV 血清阴性个体的机制研究

• 批准号: 8503631
• 负责人: Peter A Anton
• 金额: $ 36.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503631
• 关键词: Acquired Immunodeficiency Syndrome; Address; Alleles; Anti-Retroviral Agents; Antigen-Presenting Cells; Anus; Area; Behavior; Biological; Biological Factors; CCR5 gene; CD4 Positive T Lymphocytes; Cellular Immunity; Cohort Studies; Data; Defensins; Developed Countries; Development; Educational workshop; Enrollment; Epidemic; Equilibrium; Exhibits; Exposure to; Fatigue; General Population; Genetic; Genetic Polymorphism; Genetic Status; Genome; Genotype; HIV; HIV-1; HLA Antigens; Health; Immune; Immune response; Immune system; Incidence; Individual; Infection; Infection prevention; Integration Host Factors; Life; Link; Lymphocyte Activation; Metabolic; Minor; Mucous Membrane; Natural History; Natural Immunity; Pathway interactions; Pattern recognition receptor; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Predisposition; Prevention approach; Production; Property; Recruitment Activity; Relative (related person); Resistance; Resources; Risk; Signal Transduction; Single Nucleotide Polymorphism; Site; Solutions; Stimulus; Surface; Surveys; United States National Institutes of Health; Vaccination; Vaccine Design; Viral; Virus; Vulnerable Populations; adaptive immunity; base; cohort; coping; design; high risk; interest; men; men' s group; pandemic disease; rectal; resistance mechanism; success; theories; transmission process; viral resistance

DESCRIPTION (provided by applicant): As detailed in the "Request For Applications" to which this proposal responds, the mechanisms of resistance of some individuals to HIV-1 infection (highly exposed seronegative, HESN) remain poorly understood. Major questions regarding this phenomenon were raised at an NIH workshop on this topic that serves as the basis for this RFA, including: 1) What is different in HESN versus those who get infected? 2) What is the immune response in HESN and is it just a marker of exposure or a correlate of protection? 3) What are the HESN host factors that help HESN resist infection? This proposal addresses these issues by exploring the overarching hypothesis that innate immune reactivity is a key determinant of CD4+ T lymphocyte activation at mucosal surfaces, and therefore a key determinant of susceptibility to HIV-1 infection of an individual. HESN may be different in terms of innate immune reactivity, which would be a key difference in the immune response of these persons compared to the general population, and not necessarily HIV-1-specific. The host factors determining this difference likely would be genetic, which will be explored by whole genome single nucleotide polymorphism examination in a complementary study. We will pursue this hypothesis by examining a unique cohort of men in the Multicenter AIDS Cohort Study who had extremely high-risk sexual exposures in the early- to mid-1980s, yet remained uninfected. The susceptibility and reactivity of their mucosal innate immune system will be assessed using HIV-1 infection and examining the effects of defined stimuli of pattern recognition receptors. We will focus on their site of sexual exposure, the rectal mucosa. Specifically, we propose: ¿ To determine innate immune signals important for HIV-1 replication in gut mucosa and quantitate the ability of gut mucosa from HESN to support HIV-1 replication ¿ To assess the innate immune responsiveness of HESN gut mucosa to different stimuli ¿ To examine the phenotypes of antigen-presenting cells in the gut mucosa of HESN

描述(由申请人提供)：正如本提案回应的“申请申请”中详细说明的那样，一些人对艾滋病毒-1感染(高度暴露的血清阴性，HESN)的抵抗机制仍然知之甚少。关于这一现象的主要问题是在作为RFA基础的NIH研讨会上提出的，包括：1)HESN与那些感染的人有什么不同？2)HESN的免疫反应是什么，它只是暴露的标志还是保护的相关性？3)HESN的宿主因素是帮助HESN抵抗感染的？这一建议通过探索一个重要的假设来解决这些问题，即先天免疫反应性是粘膜表面CD4+T淋巴细胞激活的关键决定因素，因此也是个人感染HIV-1的关键决定因素。HESN在先天免疫反应性方面可能不同，这将是这些人与普通人群相比免疫反应的关键差异，而不一定是HIV-1特异性的。决定这种差异的宿主因素可能是遗传因素，这将在一项补充研究中通过全基因组单核苷酸多态检查来探索。我们将通过检查多中心艾滋病队列研究中的一组独特的男性来进一步研究这一假设，这些男性在20世纪80年代初至中期有过极高风险的性行为，但仍未感染。他们的粘膜天然免疫系统的敏感性和反应性将通过HIV-1感染和检查模式识别受体的特定刺激的影响来评估。我们将重点关注他们的性行为暴露部位，直肠粘膜。具体地说，我们建议：？确定肠粘膜中对HIV-1复制至关重要的先天免疫信号，并量化HESN肠粘膜支持HIV-1复制的能力？评估HESN肠粘膜对不同刺激的先天免疫反应性？检查HESN肠粘膜中抗原提呈细胞的表型