IMMUNE MODULATION AND RESTORATION IN HIV-1 INFECTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 HIV-1感染与CD 4 + T细胞的丢失、慢性免疫激活和进行性免疫功能障碍有关。艾滋病毒特异性反应在感染后早期受损，并在疾病进展为艾滋病中发挥重要作用。恢复病毒特异性免疫的免疫调节疗法可防御疾病进展。我们使用一种新的人源化小鼠模型来研究HIV-1感染的进展，并确定艾滋病相关T细胞功能障碍的免疫学靶点。将人造血CD 34+干细胞移植到新生NOD/scid-IL-2 Rgcnull免疫缺陷小鼠中发育成功能性人免疫系统。重组小鼠易受HIV-1感染，并出现与CD 4 + T细胞和免疫激活下降相关的病理学。通过流式细胞术分析外周血和淋巴组织中与免疫功能障碍相关的共抑制分子的表达，包括细胞毒性T淋巴细胞抗原4（CTLA 4）、程序性死亡-1（PD-1）及其配体PD-L1和PD-L2以及B和T细胞衰减因子（BTLA）。小鼠慢性HIV-1感染导致PD-1、BTLA和CTLA 4在人淋巴细胞上表达，PD配体在抗原呈递细胞上上调。增强对HIV-1的免疫应答的治疗方法包括阻断T细胞功能的这些负调节因子或直接靶向B细胞调节因子如CD 40以调节B细胞应答。作为调节HIV-1感染中的免疫应答的第一次尝试，我们在人源化小鼠中测试了CD 40抗体以增强B细胞功能并恢复体液免疫应答。人源化小鼠是评价临床前免疫治疗的有前景的转化模型。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV-1 infection is associated with the loss of CD4+ T cells, chronic immune activation and progressive immune dysfunction. HIV-specific responses become impaired early after infection and play a major role in disease progression to AIDS. Immuno-modulatory therapies that restore virus specific immunity may defend against the disease progression. We used a novel humanized mouse model to study the progression of HIV-1 infection and to identify the immunotherapeutic targets in AIDS related T cell dysfunction. Human hematopoietic CD34+ stem cells transplanted into new born NOD/scid-IL-2Rgcnull immunodeficient mice develop into a functional human immune system. Reconstituted mice are susceptible to HIV-1 infection and develop realated pathology with a decline in CD4+ T cells and immune activation. Expression of co-inhibitory molecules associated with immune dysfunction, including Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), Programmed Death-1 (PD-1) and its ligands PD-L1 and PD-L2, and B and T cell attenuator (BTLA), was analyzed by flow cytometry in peripheral blood and lymphoid tissues. Chronic HIV-1 infection in mice resulted in PD-1, BTLA and CTLA4 expression on human lymphocytes, and PD ligands being upregulated on antigen presenting cells. Therapeutic approaches to augment immune responses to HIV-1 include either blocking these negative regulators of T cell function or directly targeting B cell regulators such as CD40 to regulate B cell responses. As a first attempt to modulate immune responses in HIV-1 infection we tested CD40 antibody in humanized mice to augment B cell function and restore humoral immune responses. Humanized mice are promising translational models to evaluate pre-clinical immuno-therapeutics.