Identify New Determinants to Target Macrophage-Tropic Viruses and Prevent HIV-1 Brain Infection in NeuroAIDS

项目摘要/摘要 尽管进行了联合抗逆转录病毒治疗，但仍有约50%的接受治疗的患者存在认知障碍。 减损。大脑中的艾滋病毒感染会导致一系列称为艾滋病毒相关的神经认知功能障碍 神经认知障碍(HAD)与艾滋病毒相关痴呆(HAD)，是最严重的形式。有一个很高的 使用抗病毒药物治疗的艾滋病毒感染患者的数量受到手部影响，其风险增加 与年龄和心血管疾病有关。艾滋病毒在感染的早期侵入大脑。新技术的发展 避免早期和晚期脑部感染的策略将是改善艾滋病毒患者的 生活质量、生存和日常功能。 HIV通过病毒表面的包膜糖蛋白三聚体感染靶细胞。HIV三聚体是 由三种糖蛋白(Gp120)形成，它们直接与cd4受体相互作用，然后与辅助受体共同作用，从而 病毒进入目标细胞。巨噬细胞嗜性(M嗜性)病毒在大脑中复制是因为它们有 适合于利用巨噬细胞和小胶质细胞表面的少量CD4。因此，嗜M病毒 携带更多暴露的CD4b。具有更开放的CD4b的env在诱导抗体方面可能更有效。 地点。关于gp120中的每个残基如何调节CD4bs暴露的知识存在一个根本性的空白。 我们的假设是，使用带有暴露的CD4bs的三聚体env的疫苗将诱导对M- 感染大脑的热带病毒。我们的目标是确定不同HIV的新的gp120/gp41突变 传播/创始(T/F)分支，诱导CD4b暴露并表征所产生的环境 三聚体的生物学和结构特性。在强劲的初步数据指导下，我们建议：1)选择 T/F分支A、B和C三聚体与暴露的CD4bs，2)通过评估修饰来表征这些突变体 3)研究该突变对巨噬细胞感染和共受体-2的影响。 使用。这些知识对于了解M嗜性病毒如何进化以感染大脑和发育是至关重要的 诱导针对嗜M病毒的强大中和抗体的疫苗。因此，这项提议是第一次 以及合理的步骤，以生产一种有可能预防艾滋病毒形成并针对艾滋病毒的疫苗 大脑储藏室。

Project summary/Abstract Despite the combined antiretroviral therapy, around 50% of all treated patients still suffer cognitive impairments. HIV infection in the brain causes a spectrum of neurocognitive dysfunctions called HIV-associated neurocognitive disorders (HAND) with HIV-associated dementia (HAD), the most severe form. There is a high number of HIV-infected patients treated with antivirals that are affected by HAND, the risk of which increases with age and cardiovascular disease. HIV invades the brain early during the infection. The development of new strategies to avoid early and later brain infection would represent novel approaches to improve the HIV patient's quality of life, survival and everyday function. HIV infects target cells using the envelope glycoprotein trimers on the viral surface. The HIV trimer is formed by three glycoproteins (gp120) that interact directly with the CD4 receptor and then co-receptors allowing the virus entry into target cells. Macrophage tropic (M-tropic) viruses replicate in the brain because they have adapted to exploit low amounts of CD4 on the surface of macrophages and microglia. M-tropic viruses therefore carry more exposed CD4bs. Envs with a more open CD4bs may be more efficient at inducing antibodies to this site. There is a fundamental gap in knowledge of how each residue in gp120 regulates exposure of the CD4bs. Our hypothesis is that vaccines using trimeric Envs with an exposed CD4bs will induce protection against M- tropic viruses that infect the brain. Our objective here is to identify new gp120/gp41 mutations of diverse HIV Transmitted/Founder (T/F) clades that induce exposure of the CD4bs and to characterize the resulting Env trimers for their biological and structural properties. Guided by strong preliminary data, we propose: 1) to select T/F clade A, B and C trimers with exposed CD4bs, 2) to characterize these mutants by evaluating modifications in trimer structure and 3) to investigate the effect of this mutations on macrophage infection and co-receptor- use. This knowledge will be essential to understand how M-tropic viruses evolve to infect the brain and to develop vaccines that induce potent neutralizing antibodies against M-tropic viruses. This proposal thus represents a first and rational step to produce a vaccine with the potential to prevent the formation of, as well as targeting the HIV brain reservoir.