Immunoregulatory Function of Myelomonocytic Receptors in HIV-1 Infection

描述(申请人提供)：虽然HIV-1可以在几乎所有感染者中诱导强烈的抗原特异性T细胞和B细胞，但这些适应性免疫反应中的大多数并不能防止HIV-1疾病的发展。只有在极少数“精英控制者”的情况下，才能产生针对HIV-1的有效T细胞免疫活动，从而有效地阻止HIV-1复制到无法检测的水平。同样，能够广泛中和的B细胞反应 大多数流行的病毒物种和有效防止艾滋病毒-1在动物模型中的传播只出现在非常少数的个体中。然而，支持在这少数感染者中诱导如此有效的T和B细胞免疫反应的机制，而不是在大多数替代患者中，在很大程度上尚不清楚。树突状细胞(DC)是最有效的自然产生的抗原提呈细胞，具有重要作用 对于诱导抗原特异性T细胞反应，以及它们在体液免疫反应进化中的决定性作用也越来越被认识到。然而，有助于产生保护性HIV-1特异性T细胞和B细胞的DC的特定功能特征 尽管几乎所有的HIV-1候选疫苗都依赖DC来诱导适应性免疫反应，但反应尚不清楚。这项申请寻求使用一组新颖的、跨学科的方法论方法来探索这种机制。在特定的目标1中，我们建议研究人类白细胞免疫球蛋白样受体(LILR)和人类白细胞免疫球蛋白I类分子之间的免疫遗传网络。我们假设，HLAI类和LILR同种异型的特定组合可以改善DC的功能活性，并提高其产生针对HIV-1的保护性免疫反应的能力。在特定的目标2中，我们将探索精英控制者DC中针对HIV-1感染的细胞内源性免疫反应，并评估这种先天免疫活性对随后的HIV-1特异性T细胞反应功能的影响。这些研究基于大量的初步数据，表明这些患者的DC具有独特的能力，可以安装针对HIV-1的细胞固有的I型干扰素反应，并可能揭示DC的固有免疫机制和获得性免疫机制之间先前未知的网络，这对诱导高度保护性的HIV-1特异性T细胞反应至关重要。在具体目标3中，我们将探索少数自然产生针对HIV-1的广谱中和抗体(BNAb)/中和宽度(Nb)的树突状细胞的功能特性，并通过启动特定人群的T滤泡辅助细胞反应来研究树突状细胞中支持bNAb/NB发育的分子信号。通过确定树突状细胞在自然感染期间对产生有效的抗HIV-1免疫反应至关重要的特定功能方面，这项工作将有助于设计在更大的患者群体中诱导这种免疫反应的策略。

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.