HIV-related blood dendritic cell dysfunction

描述（由申请人提供）：HIV-1感染的特征是进行性CD4+ T细胞破坏，抗原特异性CD4+和CD8+ T细胞功能障碍，慢性免疫激活。尽管hiv -1特异性T细胞反应通常在感染早期产生，但它们在体内逐渐失去抑制病毒复制的能力。结果是大多数受感染的人都染上了艾滋病。树突状细胞（dc）是抗原特异性T细胞的有效刺激物，也可能促进T细胞的稳态。DC功能由DC类型和有序的激活过程（称为“成熟”）决定。血液树突状细胞（bdc）是在组织和淋巴器官中发现的循环未成熟的树突状细胞前体，根据表型和功能的差异，可分为两大亚群，髓样树突状细胞（mDCs）和浆细胞样树突状细胞（pDCs）。两种DC亚群都被认为可以刺激HIV-1特异性细胞介导的免疫，而pDCs可能通过直接抗病毒特性抑制HIV-1复制。然而，我们和其他人观察到hiv感染受试者中循环BDC亚群的数量和功能都存在缺陷。此外，我们观察到病毒血症患者bdc上共刺激分子的不完全上调和趋化因子受体的表达改变，表明成熟失调。重要的是，在高活性抗逆转录病毒治疗（HAART）抑制HIV-1复制6个月后，这些DC异常未能正常化。尽管抗原提呈细胞（APC）功能缺陷与HIV-1发病机制有关，但HIV相关BDC异常对HAART前后T细胞功能和免疫恢复程度的影响尚未得到充分评估。为了了解HIV-1改变DC成熟的机制以及DC功能障碍对T细胞功能的影响，我们特别提出：1)确定体内HIV-1复制是否会改变趋化因子受体的表达、迁移反应以及血液中pDCs和mDCs的内噬能力；2)确定体内HIV-1复制是否与淋巴组织中pDCs和mDCs的积累有关；3)比较未感染和HIV-1感染受试者的bdc对回忆ag特异性记忆CD4+和CD8+ T细胞群的刺激。4)研究hiv -1感染与未感染受试者获得的bdc在体外诱导自体幼稚和记忆CD4+ T细胞亚群增殖的能力。这些研究的结果应该有助于开发旨在恢复DC数量和功能的治疗方法，从而导致更完全的免疫恢复。

DESCRIPTION (provided by applicant): HIV-1 infection is marked by progressive CD4+ T cell destruction, antigen-specific CD4+ and CD8+ T cell dysfunction, and chronic immune activation. Although HIV-1-specific T cell responses are often generated early in infection, they progressively lose the ability to suppress viral replication in vivo. The result is AIDS in the majority of infected individuals. Dendritic cells (DCs) are potent stimulators of antigen-specific T cells and may also facilitate T cell homeostasis. DC function is determined both by DC type and an ordered process of activation, termed "maturation." Blood dendritic cells (BDCs), circulating immature precursors of DCs found in tissues and lymphoid organs, can be categorized into two major subpopulations, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), based on differences in phenotype and function. Both DC subsets are postulated to stimulate HIV-1-specific cell-mediated immunity, and pDCs may suppress HIV-1 replication via direct antiviral properties. However, we and others observed defects in both the number and function of circulating BDC subsets in HIV-infected subjects. Furthermore, we observed incomplete upregulation of costimulatory molecules and altered expression of chemokine receptors on BDCs in viremic subjects, suggesting dysregulated maturation. Importantly, these DC abnormalities failed to normalize after 6 months of suppression of HIV-1 replication with highly active antiretroviral therapy (HAART). Although defective antigen presenting cell (APC) function has been implicated in HIV-1 pathogenesis, the impact of HIV- associated BDC abnormalities on the extent of T cell function and immune recovery before and after HAART have not been fully evaluated. To understand the mechanisms by which HIV-1 alters DC maturation and the implications of DC dysfunction on T cell function, we specifically propose: 1) to determine whether HIV-1 replication in vivo alters chemokine receptor expression, migratory responses, and endocytic capacity of blood pDCs and mDCs, 2) to determine whether HIV-1 replication in vivo is associated with an accumulation of pDCs and mDCs in lymphoid tissue, 3) to compare stimulation of recall Ag-specific memory CD4+ and CD8+ T cell populations by BDCs from uninfected and HIV-1-infected subjects, 4) to investigate the ability of BDCs obtained from HIV-1-infected versus uninfected subjects to induce proliferation of autologous naive and memory CD4+ T cell subsets in vitro. The results of these studies should facilitate development of therapies designed to restore DC number and function, thus leading to more complete immune recovery.