HIV-related blood dendritic cell dysfunction

描述(申请人提供)：HIV-1感染的标志是进行性的CD4+T细胞破坏，抗原特异性的CD4+和CD8+T细胞功能障碍，以及慢性免疫激活。尽管HIV-1特异性T细胞反应通常在感染早期产生，但它们逐渐失去了抑制体内病毒复制的能力。其结果是大多数感染艾滋病的人感染了艾滋病。树突状细胞(DC)是抗原特异性T细胞的强大刺激物，也可能促进T细胞的动态平衡。DC功能由DC类型和有序的激活过程决定，称为“成熟”。血树突状细胞(BDC)是存在于组织和淋巴器官中的DC的未成熟前体细胞，根据其表型和功能的不同，可分为髓系树突状细胞(MDCS)和浆细胞样树突状细胞(PDCs)。这两个DC亚群都被认为是刺激HIV-1特异性细胞免疫，pDC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感染者循环中的BDC亚群在数量和功能上都存在缺陷。此外，我们观察到在病毒症受试者的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，这表明成熟调节失调。重要的是，在用高效抗逆转录病毒疗法(HAART)抑制HIV-1复制6个月后，这些DC异常未能恢复正常。尽管抗原提呈细胞(APC)功能缺陷与HIV-1的致病机制有关，但HAART前后HIV相关的BDC异常对T细胞功能和免疫恢复的影响尚未得到充分评价。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HIV-1体内复制是否改变血液PDCs和MDCs的趋化因子受体表达、迁移反应和内吞能力；2)确定HIV-1体内复制是否与PDCs和MDCs在淋巴组织中的聚集有关；3)比较未感染和HIV-1感染者的BDC对Recall Ag特异性记忆CD4+和CD8+T细胞群的刺激。4)研究HIV-1感染者与未感染者的BDC体外诱导自体幼稚和记忆性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.