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 HIV 靶向脂质体疫苗生成强效抗 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，每年都会有数千例新感染病例 虽然抗逆转录病毒疗法 (ART) 的进步延长了患者的寿命，但 ART 并没有延长患者的寿命。 治愈艾滋病毒感染，使依赖抗逆转录病毒疗法的患者收效甚微。 在此，我们提出了针对 HIV 的免疫逃避、高变异性和潜在病毒库的新策略。 治疗性 HIV 疫苗，Nanotrap 治疗疫苗 (NTV) 是由以下成分组成的改良脂质体。 结合 gp120 和/或 gp41 的 HIV 靶向分子以及扭曲先天免疫反应的佐剂 针对 Th1 和 CD8+ T 细胞反应的 NTV 被设计为在 HIV 感染后注射，但同时进行。 当循环病毒载量较高时，进行 ART 治疗时，NTV 会结合循环中的 HIV 并被 HIV 吞噬。 局部 APC，从而将 HIV 病毒颗粒和佐剂共同递送至 APC，激活它们。 HIV+先天免疫细胞将运输到淋巴结并刺激HIV特异性CD8+T细胞，这可以 消灭潜伏病毒。 该提案有两个目标。首先，我们将通过从库中进行选择来优化 NTV 的 HIV 结合部分。 利用已知的 gp120 和 gp41 靶向分子（通常用于抑制 HIV 病毒进入），我们可以合成脂质 配方，将它们纳入脂质体，优化其配方并验证它们与 HIV 和 其次，在筛选出潜在的 Th1 倾斜佐剂后，我们将灭活病毒。 配制负载佐剂的 NTV，并验证这些 NTV 是否被局部先天免疫细胞吸收，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) NTV。 选择性产生效应 T 细胞反应，已被证明可以消除潜伏的病毒库；2) NTV 可以在每位患者体内产生针对循环病毒的特异性免疫反应，从而克服 HIV 的高感染率 如果成功，该提议将产生一种新型的艾滋病毒疫苗和疫苗。 可能是治愈艾滋病毒的第一步。