A systems biology approach to fingerprint HIV immune defense in Elite Controllers

描述（由申请人提供）：设计有效的预防性HIV-1疫苗的主要障碍仍然是我们对HIV-1免疫防御机制的了解不足。精英控制者是一小部分患者，他们自发地将HIV-1复制控制在无法检测的水平，可以说是研究有效的宿主限制机制对抗HIV-1的最佳体内人类模型，这些患者已经进入当前努力的中心，以确定免疫保护的相关因素，这些相关因素可以用作HIV-1疫苗设计的蓝图。在先前的研究中，对这些患者的抗菌免疫防御机制的研究主要集中在宿主防御机制的个体方面，如T细胞或B细胞介导的免疫反应；然而，现在很清楚，在精英控制者中有效限制HIV-1复制可能涉及

DESCRIPTION (provided by applicant): The preeminent roadblock to the design of an effective preventative HIV-1 vaccine remains our insufficient understanding of immune defense mechanisms that protect against HIV-1. Elite controllers, a small group of patients who spontaneously control HIV-1 replication to undetectable levels, arguably represent the best in vivo human model for studying effective host restriction mechanisms against HIV-1, and these patients have moved into the center of current efforts to identify correlates of immune protection that can be used as a blueprint for HIV-1 vaccine design. In prior studies, investigations on antimicrobial immune defense mechanisms in these patients have focused on individual aspects of host defense mechanisms, such as T- or B- cell mediated immune responses; however, it is now clear that effective restriction of HIV-1 replication in elite controllers is likely to involve numerous additional innate and cell-intrinsic immune defense mechanisms, and that a complex, fine-tuned interplay between multiple different components and compartments of the immune system is responsible for the ability of these persons to spontaneously control HIV-1 infection. Yet, such integrated programs can hardly be detected using traditional reductionist approaches that are biased towards specific previously-defined molecules or investigate one specific aspect of immune defense in an isolated fashion. Systems biology has emerged as a novel integrative methodology that aims at combining global, unbiased data to detect synergistic molecular networks that are associated with and predictive of specific clinical disease outcomes. In this application, an interdisciplinary group of investigators with complementary backgrounds in functional immunology, virology, genomics, transcriptomics, biocomputational modeling and clinical HIV-1 patient care propose to rigorously apply this novel methodology by integrating global, unbiased genetic and transcriptional profiling techniques with functional immunology and virology studies to identify previously unrecognized mechanisms of immune defense against HIV-1 in elite controllers. In specific aim 1, we will generate a unique, first-of-its-kind datasetthat includes comprehensive information on the genetic, gene expression and functional immunologic and virologic characteristics of such patients. Using a combination of different biocomputational algorithms, this data will subsequently be used to detect integrated, multi-system programs of immune protection that are operational in these patients (specific aim 2). These signatures of immune protection will then be tested for their ability to prospectively predict clinical HIV-1 disease outcomes in a cohort of untreated HIV-1 patients identified during primary HIV-1 infection (specific aim 3). This novel methodological approach has the clear potential for revealing previously-unrecognized programs of HIV-1 immune defense in elite controllers, and may substantially increase our conceptual understanding of effective HIV-1 immune protection. Eventually, the identification of a set of different parameters associated with viral control in elite controllers may represent the referential frame for what may be needed in an effective HIV-1 vaccine.