Immunoregulatory Function of Myelomonocytic Receptors in HIV-1 Infection

描述（由申请人提供）：尽管HIV-1可以在几乎所有感染个体中诱导强抗原特异性T细胞和B细胞，但这些适应性免疫应答中的大多数对HIV-1疾病进展没有保护作用。只有在非常罕见的情况下，“精英控制者”，有效的T细胞免疫活性对HIV-1的产生，可以有效地阻止HIV-1复制到无法检测的水平。同样，B细胞反应能够广泛地中和 大多数循环病毒种类和有效防止HIV-1在动物模型中的传播只出现在极少数个体中。然而，支持在这少数感染个体中诱导这种有效的T细胞和B细胞免疫应答，而不是在大多数替代患者中诱导这种有效的T细胞和B细胞免疫应答的机制在很大程度上尚不清楚。树突状细胞（Dendritic cells，DCs）是自然界中最有效的抗原提呈细胞，具有重要作用 用于诱导抗原特异性T细胞应答，并且它们对体液免疫应答的进化的决定性影响也越来越被认识到。然而，在产生保护性HIV-1特异性T细胞和B细胞中起作用的DC的特定功能特征， 尽管事实上几乎所有的HIV-1候选疫苗都依赖于DC来诱导适应性免疫应答，但免疫应答的情况尚不清楚。本申请旨在探索这种机制，使用一组新颖的，跨学科的方法。在具体的目标1中，我们建议研究HLA I类分子和白细胞免疫球蛋白样受体（LILR），一组免疫调节MHC I类受体表达的DC之间的免疫遗传网络。我们假设HLA I类和LILR同种异型的特定组合导致DC的功能活性改善，以及它们产生针对HIV-1的保护性免疫应答的能力。在具体目标2中，我们将探索精英控制者DC中针对HIV-1感染的细胞内在免疫应答，并评估这种先天免疫活性对随后HIV-1特异性T细胞应答功能的影响。这些研究是基于大量的初步数据，证明了这些患者的DC具有独特的能力，能够对抗HIV-1的细胞内在I型干扰素应答，并可能揭示了DC中先天性和适应性免疫机制之间先前未被认识的网络，这对于诱导高度保护性HIV-1特异性T细胞应答至关重要。在具体目标3中，我们将探索少数自然产生针对HIV-1的广泛中和抗体（bNAb）/中和宽度（NB）的个体中DC的功能特性，并研究DC中通过引发特定T滤泡辅助细胞应答群体来支持bNAb/NB发展的分子信号。通过确定特定的功能方面的DC，是至关重要的产生有效的免疫反应，对HIV-1在自然感染，这项工作将有助于设计的策略，以诱导这种免疫反应，在更大的患者群体。

DESCRIPTION (provided by applicant): Although HIV-1 can induce strong antigen-specific T- and B-cells in almost all infected individuals, most of these adaptive immune responses are not protective against HIV-1 disease progression. Only in the very rare cases of "elite controllers", effective T cell immune activity against HIV-1 is generated that can effectively block HIV-1 replication to undetectable levels. Similarly, B-cell responses that are able to broadly neutralize the majority of circulating viral species and effectively prevent HIV-1 transmission in animal models only emerge in a very small number of individuals. Yet, the mechanisms that support induction of such effective T- and B-cell immune responses in this small number of infected individuals, but not in the majority of alternative patients, are largely unclear. Dendritic cells (DCs) represent the most effective naturally-occurring antigen-presenting cells with critical roles for inducing antigen-specific T cell responses, and their decisive impact on the evolution of humoral immune responses is also increasingly being recognized. However, specific functional characteristics of DCs that are instrumental in generating protective HIV-1-specific T- and B- cell responses are unclear, despite the fact that almost all HIV-1 vaccine candidates rely on DCs for induction of adaptive immune responses. This application seeks to explore such mechanisms using a panel of novel, interdisciplinary methodological approaches. In specific aim 1, we propose to investigate the immunogenetic network between HLA class I molecules and Leukocyte Immunoglobulin-Like Receptors (LILR), a group of immunomodulatory MHC class I receptors expressed on DCs. We hypothesize that specific combinations of HLA class I and LILR allotypes result in improved functional activities of DCs, and their abilities to generate protective immune responses against HIV-1. In specific aim 2, we will explore cell-intrinsic immune responses against HIV-1 infection in DCs from elite controllers, and evaluate the influence of such innate immune activity on the function of ensuing HIV-1-specific T cell responses. These investigations are based on a large set of preliminary data demonstrating unique abilities of DCs from these patients to mount cell-intrinsic type I interferon responses against HIV-1, and may reveal a previously unrecognized network between innate and adaptive immune mechanisms in DCs that is critical for the induction of highly-protective HIV-1-specific T cell responses. In specific aim 3, we will explore functional properties of DCs in the small number of individuals who naturally develop broadly-neutralizing antibodies (bNAb)/neutralizing breadth (NB) against HIV-1, and investigate molecular signals in DCs that support bNAb/NB development through priming of specific populations of T follicular helper cell responses. By identifying specific functional aspects of DCs that are critical for the generation of effective immune responses against HIV-1 during natural infection, this work will contribute to the design of strategies to induce such immune responses in larger patient populations.