Generating Robust anti-HIV CD8 T cells using HIV-targeted Liposomal Vaccines

使用 HIV 靶向脂质体疫苗生成强效抗 HIV CD8 T 细胞

• 批准号: 10882236
• 负责人: Peter Deak
• 金额: $ 48.59万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882236
• 关键词: Adjuvant; Antibody Response; Antigen-Presenting Cells; Azoles; B-Lymphocytes; Binding; Biodistribution; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Culture Techniques; Cells; Circulation; Cross Presentation; Engineering; Ensure; Epitopes; Formulation; Frustration; Generations; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Hepatitis; Human; Immune; Immune Evasion; Immune response; Immunity; Immunologic Adjuvants; Immunologic Stimulation; In Vitro; Infection; Innate Immune Response; Kinetics; Libraries; Lipids; Liposomes; Longevity; Measures; Modeling; Molecular; Monitor; Mus; Mutation; Nanotrap; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phagocytosis; Physiological; Plasma; Public Health; Research; Rest; Sampling; Surface; System; T cell response; T memory cell; Testing; Tissues; Vaccination; Vaccine Design; Vaccine Therapy; Vaccines; Variant; Viral; Viral Load result; Virus; Virus Latency; Virus Receptors; antiretroviral therapy; design; effective therapy; effector T cell; glycosylation; improved; in vivo; innovation; lymph nodes; mortality; mouse model; novel therapeutic intervention; novel therapeutics; particle; prevent; response; screening; success; therapeutic vaccine; uptake; vaccination strategy; vaccine acceptance; weapons

Generating Robust anti-HIV CD8 T cells using HIV-targeted Liposomal Vaccines Project Summary: HIV remains a major public health issue in the US, with thousands of new infections every year. While advancements in anti-retroviral therapies (ART) have increased patient lifespans, ART does not cure HIV infection, leaving patients reliant upon ARTs. HIV vaccines have had little success, owing to the immune evasion, high mutability, and latent viral depots of HIV. Here, we propose a new strategy for therapeutic HIV vaccines, the Nanotrap Therapeutic Vaccine (NTV). NTVs are modified liposomes consisting of HIV targeting molecules that bind gp120 and/or gp41 and adjuvants that skew innate immune responses toward Th1 and CD8+ T cell responses. NTVs are designed to be injected after HIV infection, but concurrent with ART therapy when circulating viral loads are high. NTV will bind circulating HIV and be phagocytosed by local APCs, thereby co-delivering both HIV viral particle and adjuvant to APCs, activating them. The activated HIV+ innate immune cell will traffic to the lymph node and stimulate HIV specific CD8+ T cells, which can eradicate latent viruses. This proposal has two aims. First, we will optimize the HIV binding moiety of NTVs. By selecting from a library of known gp120 and gp41 targeting molecules, typically used to inhibit HIV viral entry, we can synthesize lipid formulations, incorporate them into liposomes, optimize their formulation and verify that these bind HIV and inactivate the virus from infecting other cells. Second, after screening potential Th1 skewing adjuvants, we will formulate adjuvant loaded NTVs and verify that these are taken up by local innate immune cells and can generate anti-HIV CD8+ T cell responses both in vitro and in vivo. This project is innovative because 1) NTVs selectively generate effector T cell responses, which have been shown to eliminate latent viral depots and 2) NTVs can generate immune responses specific to the circulating virus in each patient, overcoming HIV’s high mutability evasion strategy. If successful, this proposal would generate a new class of HIV vaccine and potentially be the first step to curing HIV.

使用靶向HIV的脂质体疫苗生成健壮的抗HIV CD8 T细胞 项目摘要：艾滋病毒仍然是美国的一个主要公共卫生问题，每次都有成千上万的新感染 年。虽然抗逆转录病毒疗法的进步（ART）的患者寿命增加，但艺术却没有 治愈艾滋病毒感染，使患者依赖于艺术。艾滋病毒疫苗几乎没有成功，因此 艾滋病毒的免疫进化，高可突变性和潜在病毒沉积。在这里，我们提出了一种新的策略 治疗性HIV疫苗，纳米rap治疗疫苗（NTV）。 NTV是修饰的脂质体 结合gp120和/或gp41的艾滋病毒靶向分子以及偏你的固有免疫反应的调节器 朝向Th1和CD8+ T细胞反应。 NTV被设计为在HIV感染后注射，但并发 当循环病毒负荷高时，使用艺术疗法。 NTV将结合循环HIV并通过 局部APC，从而将HIV病毒颗粒并调整为APC，从而激活它们。激活 HIV+先天性免疫细胞将流动到淋巴结并刺激HIV特异性CD8+ T细胞，这可以 消除潜在病毒。 该提议有两个目标。首先，我们将优化NTV的HIV结合部分。通过从库中选择 通常用于抑制HIV病毒进入的已知GP120和GP41靶向分子的靶向分子，我们可以合成脂质 公式将它们纳入脂质体，优化其公式，并验证这些结合HIV和 从感染的其他细胞中灭活病毒。第二，在筛选潜在的Th1偏斜调节器之后，我们将 制定调整加载的NTV，并验证它们是否被局部先天免疫细胞占用，并且可以 在体外和体内产生抗HIV CD8+ T细胞反应。该项目具有创新性，因为1）NTVS 有选择地产生效应T细胞反应，已证明可以消除潜在的病毒沉积物，而2） NTV可以在每位患者中产生特有循环病毒的免疫复杂，从而克服了艾滋病毒的高 可突变性演化策略。如果成功，该提案将产生新的HIV疫苗，并 可能是治愈艾滋病毒的第一步。