HIV-related blood dendritic cell dysfunction

描述（由申请方提供）：HIV-1感染的特征是进行性CD 4 + T细胞破坏、抗原特异性CD 4+和CD 8 + T细胞功能障碍以及慢性免疫激活。虽然HIV-1特异性T细胞反应通常在感染早期产生，但它们逐渐失去抑制体内病毒复制的能力。其结果是艾滋病在大多数受感染的人。树突状细胞（DC）是抗原特异性T细胞的有效刺激物，也可以促进T细胞稳态。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），在组织和淋巴器官中发现的DC的循环未成熟前体，可以根据表型和功能的差异分为两个主要亚群，髓样DC（mDC）和浆细胞样DC（pDC）。假设两种DC亚群都刺激HIV-1特异性细胞介导的免疫，并且pDC可以通过直接的抗病毒特性抑制HIV-1复制。然而，我们和其他人观察到HIV感染者循环BDC亚群的数量和功能都存在缺陷。此外，我们观察到不完全上调共刺激分子和改变表达的趋化因子受体的BDC在病毒血症的主题，表明失调的成熟。重要的是，这些DC异常未能正常化后，6个月的抑制HIV-1复制与高效抗逆转录病毒治疗（HAART）。虽然缺陷的抗原呈递细胞（APC）功能与HIV-1发病机制有关，但HIV相关的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）确定体内HIV-1复制是否改变血液pDC和mDC的趋化因子受体表达、迁移反应和内吞能力，2）确定体内HIV-1复制是否与淋巴组织中pDC和mDC的积累相关，3）比较来自未感染和HIV-1感染受试者的BDC对回忆Ag特异性记忆CD 4+和CD 8 + T细胞群的刺激，4）研究从HIV-1感染与未感染受试者获得的BDC体外诱导自体幼稚和记忆CD 4 + 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数量和功能的疗法，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.