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.

利用HIV靶向脂质体疫苗产生强大的抗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，每年有数千人新感染 年。虽然抗逆转录病毒疗法(ART)的进步延长了患者的寿命，但ART并非如此 治愈艾滋病毒感染，让患者依赖抗逆转录病毒治疗。艾滋病毒疫苗收效甚微，原因是 免疫逃避、高度变异性和潜伏的艾滋病毒病毒库。在这里，我们提出了一个新的战略，以 治疗性艾滋病毒疫苗，纳米陷阱治疗性疫苗(NTV)。NTV是一种改良型脂质体，含有 结合gp120和/或gp41的HIV靶向分子和扭曲先天免疫反应的佐剂 Th1和CD8+T细胞应答。NTV被设计为在感染HIV后注射，但同时发生 在循环病毒载量高的情况下进行ART治疗。NTV将结合循环中的HIV并被吞噬 局部APC，从而将HIV病毒颗粒和佐剂共同传递给APC，激活它们。被激活的 HIV+先天免疫细胞会流向淋巴结，刺激HIV特异的CD8+T细胞，这可以 根除潜伏病毒。 这项提议有两个目的。首先，我们将优化NTV的HIV结合部分。通过从库中进行选择 在已知的gp120和gp41靶向分子中，通常用于抑制HIV病毒的进入，我们可以合成脂质 制剂，将它们合并到脂质体中，优化它们的配方，并验证它们与艾滋病毒和 使病毒不能感染其他细胞。第二，在筛选潜在的Th1偏斜佐剂后，我们将 制定佐剂负载的NTV，并验证它们是否被当地的先天免疫细胞摄取，并可以 在体外和体内产生抗HIV CD8+T细胞反应。这个项目是创新的，因为1)NTV 选择性地产生效应性T细胞反应，已被证明可以消除潜伏的病毒库和2) NTV可以在每个患者身上产生针对循环病毒的免疫反应，克服HIV的高 变种规避策略。如果成功，这项提议将产生一种新的艾滋病毒疫苗，并 有可能成为治愈艾滋病毒的第一步。