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

确定针对巨噬细胞嗜性病毒并预防神经艾滋病中 HIV-1 脑部感染的新决定因素

基本信息

批准号：
10370309
负责人：
Maria Jose Duenas-Decamp
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-05 至 2024-03-31
项目状态：
已结题

项目摘要

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.

项目摘要/摘要尽管进行了抗逆转录病毒疗法，但所有治疗患者中约有50％仍然患有认知障碍。大脑中的HIV感染引起了一系列称为HIV相关的神经认知功能障碍具有HIV相关痴呆的神经认知障碍（手）是最严重的形式。有一个高受到手动影响的抗病毒药治疗的艾滋病毒感染的患者数量，其风险增加随着年龄和心血管疾病。 HIV在感染期间早期入侵大脑。新的发展避免早期和晚期感染的策略将代表改善艾滋病毒患者的新方法生活质量，生存和日常功能。 HIV使用病毒表面上的包膜糖蛋白三聚体感染靶细胞。艾滋病毒夹子是由三种与CD4受体直接相互作用的糖蛋白（GP120）形成的病毒进入靶细胞。巨噬细胞的热带（M-热带）病毒在大脑中复制，因为它们具有适应巨噬细胞和小胶质细胞表面上的低量CD4。因此，M-热病毒携带更多裸露的CD4B。 Envs具有更开放的CD4B，可能更有效地诱导此抗体地点。了解GP120中每个残基如何调节CD4B的暴露的知识存在根本的差距。我们的假设是，使用三聚体环境进行暴露CD4B的疫苗将诱导防止M- 感染大脑的热带病毒。我们的目的是确定新的GP120/GP41不同艾滋病毒的突变传输/创始人（T/F）进化枝，可引起CD4B的暴露并表征所得的Env 其生物学和结构特性的三聚体。在强大的初步数据的指导下，我们建议：1）选择 t/f进化枝A，B和C型三聚体具有暴露的CD4BS，2）通过评估修改来表征这些突变体在三聚体结构和3）中研究这种突变对巨噬细胞感染和共受体的影响使用。这些知识对于了解M向M-冰球病毒如何发展以感染大脑和发展至关重要。诱导针对M-热带病毒的有效中和抗体的疫苗。因此，该建议代表了第一个和合理的步骤，生产一种疫苗，以防止形成并靶向艾滋病毒脑部储层。