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

使用HIV靶向脂质体疫苗产生稳健的抗HIV CD8 T细胞 艾滋病毒仍然是美国的一个主要公共卫生问题，每年有数千例新感染。 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并没有 治愈艾滋病毒感染，使患者依赖于抗逆转录病毒疗法。艾滋病毒疫苗几乎没有成功，因为 免疫逃避、高突变性和HIV的潜伏病毒库。在这里，我们提出了一个新的战略， 纳米陷阱治疗性疫苗（Nanotrap Therapeutic Vaccine，NTV）NTV是修饰的脂质体， 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 Th1和CD8 + T细胞反应。NTV被设计为在HIV感染后注射，但同时 当循环病毒载量高时进行ART治疗。NTV将结合循环的HIV并被 局部APC，从而将HIV病毒颗粒和佐剂共同递送至APC，激活它们。活性 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，其可以 消灭潜伏的病毒 这项建议有两个目的。首先，我们将优化NTV的HIV结合部分。通过从库中选择 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 制剂，将其掺入脂质体，优化其制剂并验证其结合HIV和 阻止病毒感染其他细胞。其次，在筛选潜在的Th1偏斜佐剂后，我们将 配制负载佐剂的NTV，并验证这些NTV被局部先天免疫细胞摄取， 在体外和体内产生抗HIV CD8 + T细胞应答。这个项目是创新的，因为1）NTV 选择性地产生效应T细胞应答，其已显示消除潜伏病毒库，和2） NTV可以在每个患者体内产生针对循环病毒的免疫反应，克服HIV的高 可变性规避策略如果成功，这一提议将产生一种新的艾滋病毒疫苗， 这可能是治愈艾滋病的第一步。

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.