Mechanistic Studies of HIV-exposed Seronegative Individuals

描述（由申请人提供）：正如本提案所回应的“申请请求”中所详述的，对某些个体对HIV-1感染（高度暴露血清阴性，HESN）的耐药机制仍知之甚少。关于这一现象的主要问题是在美国国立卫生研究院关于这一主题的研讨会上提出的，该研讨会作为RFA的基础，包括：1）HESN与感染者有什么不同？2)HESN中的免疫反应是什么？它只是暴露的标志物还是保护的相关物？3)什么是HESN的宿主因子，帮助HESN抵抗感染？该提案通过探索先天免疫反应性是粘膜表面CD 4 + T淋巴细胞活化的关键决定因素，因此是个体对HIV-1感染易感性的关键决定因素的总体假设来解决这些问题。HESN可能在先天免疫反应性方面不同，这将是这些人与普通人群相比免疫反应的关键差异，并且不一定是HIV-1特异性的。决定这种差异的宿主因素可能是遗传性的，这将在一项补充研究中通过全基因组单核苷酸多态性检测来探索。我们将通过研究多中心艾滋病队列研究中的一个独特的男性队列来探讨这一假设，这些男性在20世纪80年代早期至中期有极高风险的性暴露，但仍然没有感染。将使用HIV-1感染并检查模式识别受体的限定刺激的影响来评估其粘膜先天免疫系统的易感性和反应性。我们将重点关注他们的性暴露部位，直肠粘膜。具体而言，我们建议：¿确定肠粘膜中对HIV-1复制重要的先天免疫信号，并定量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应答;检查HESN肠粘膜中抗原呈递细胞的表型。

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