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（由应用程序提供）：如“申请请求”中所述，该提案响应，某些个体对HIV-1感染的抵抗机制（高度暴露的血清神经，HES）仍然知之甚少。关于这种现象的主要问题是在NIH的关于此主题的NIH研讨会上提出的，该主题是该RFA的基础，包括：1）HES与被感染的人有什么不同？ 2）HES中的免疫响应是什么，它只是暴露的标志或保护的标志吗？ 3）HESN宿主因素有助于HES抵抗感染？该提案通过探索了总体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，因此确定了对个体HIV-1感染的易感性的关键。 HESN在先天免疫反应性方面可能有所不同，这将是这些人的免疫反应性的关键区别，而不是普通人群，而不一定是HIV-1特异性的。确定这种差异的宿主因素可能是遗传的，在一项完整的研究中，将通过整个基因组单核苷酸多态性检查来探索。我们将通过研究多中心艾滋病队列研究中的一群人来提出这一假设，他们在1980年代初至1980年代中期进行了极高的风险性暴露，但仍未感染。其粘膜先天免疫系统的敏感性和反应性将使用HIV-1感染评估，并检查模式识别受体定义的刺激的影响。我们将专注于他们的性暴露部位，直肠粘膜。具体而言，我们提出：“确定对HIV-1复制重要的先天免疫信号，并量化肠粘膜从HESN中的肠粘膜的能力，以支持HIV-1复制�评估Hesn肠道粘膜的先天免疫反应，以不同于刺激的刺激效果，从