Characterization and restoration of exhausted immune responses in humanized Bone marrow-liver-thymus (BLT) mice infected with HIV-1

 描述（由申请人提供）：细胞免疫应答在控制HIV感染个体的病毒复制中起关键作用。然而，HIV病毒采用多种机制逃避免疫系统，并且宿主最终未能控制病毒复制，导致AIDS的发展。慢性炎症和持续的病毒复制可能导致免疫衰竭，其特征是对HIV的抗病毒反应较差。该提案的主要目的是：1）描述慢性HIV感染期间免疫功能障碍和衰竭的机制; 2）使用人源化小鼠模型探索恢复或预防免疫衰竭和改善病毒控制的各种策略。这些策略包括1）通过抗体阻断或shRNA敲低靶向激活抑制分子Tim-3和PD-1信号传导;和2）靶向持续的I型IFN信号传导以减少导致免疫衰竭的免疫抑制因子的产生。这项研究将确定T细胞耗竭的潜在机制，并为未来旨在治疗慢性HIV感染的免疫疗法提供关键信息。

 DESCRIPTION (provided by applicant): Cellular immune responses play a crucial role in controlling viral replication in HIV- infected individuals. However, HIV virus adopts numerous mechanisms to evade the immune system and the host ultimately fails to control the viral replication leading to development of AIDS. Chronic inflammation and ongoing viral replication may lead to immune exhaustion, which is characterized by poor anti-viral responses against HIV. The major aims of the proposal are to 1) characterize the mechanisms of immune dysfunction and exhaustion during chronic HIV infection and 2) explore various strategies to restore or prevent immune exhaustion and improve viral control using the humanized mice model. The strategies include 1) targeting activation inhibitory molecules Tim-3 and PD-1 signaling by antibody blockade or shRNA knock down; and 2) targeting persistent type I IFN signaling to reduce the production of immunosuppressive factors that contribute to immune exhaustion. This study will identify underlying mechanisms for T cell exhaustion and provide key information for future immune based therapies aimed at treating chronic HIV infection.