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

• 批准号: 9893028
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-05 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893028
• 关键词: AIDS dementia; Affect; Age; Amino Acids; Animal Model; Antibodies; Antigens; Antiviral Agents; Binding Sites; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; CCR5 gene; CD4 Antigens; Cardiovascular Diseases; Cells; Codon Nucleotides; Complex; Data; Dependence; Development; Epitopes; Evolution; Functional disorder; Future; Glycoproteins; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Immune; Impaired cognition; Individual; Infection; Infection prevention; Invaded; Investigation; Knowledge; Libraries; Maintenance; Maps; Methods; Microglia; Modification; Molecular Conformation; Monoclonal Antibodies; Mutagenesis; Mutation; Neurocognitive; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Production; Property; Public Health; Quality of life; Randomized; Regulation; Research; Site; Structure; Surface; Testing; Tissues; Tropism; V3 Loop; Vaccines; Variant; Viral; Virus; Virus Replication; acute infection; antiretroviral therapy; disorder risk; improved; macrophage; mutant; neuroAIDS; neutralizing antibody; novel; novel strategies; prevent; receptor; vaccine trial

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.

项目概要/摘要 尽管进行了联合抗逆转录病毒治疗，但大约 50% 的接受治疗的患者仍然患有认知障碍 损伤。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 (HAND) 与 HIV 相关痴呆 (HAD) 是最严重的形式。有一个高 接受抗病毒药物治疗的 HIV 感染患者中受到 HAND 影响的人数，其风险增加 与年龄和心血管疾病有关。 HIV 在感染早期就侵入大脑。新的发展 避免早期和晚期脑部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利用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，直接与 CD4 受体相互作用，然后与共受体相互作用 病毒进入靶细胞。嗜巨噬细胞（M-tropic）病毒在大脑中复制，因为它们具有 适合利用巨噬细胞和小胶质细胞表面的少量 CD4。因此，M向性病毒 携带更多暴露的 CD4b。具有更开放的 CD4b 的 Env 可能更有效地诱导针对此的抗体 地点。关于 gp120 中的每个残基如何调节 CD4b 暴露的知识存在根本性的差距。 我们的假设是，使用三聚体 Env 和暴露的 CD4b 的疫苗将诱导针对 M-的保护。 感染大脑的热带病毒。我们的目标是识别不同 HIV 的新 gp120/gp41 突变 诱导 CD4b 暴露并表征所得 Env 的传播/创始人 (T/F) 进化枝 三聚体的生物学和结构特性。在强有力的初步数据的指导下，我们建议：1）选择 具有暴露的 CD4b 的 T/F 进化枝 A、B 和 C 三聚体，2) 通过评估修饰来表征这些突变体 三聚体结构，3) 研究该突变对巨噬细胞感染和共受体的影响 使用。这些知识对于理解 M-tropic 病毒如何进化以感染大脑并发展为至关重要 诱导针对 M-tropic 病毒的有效中和抗体的疫苗。因此，该提案代表了第一个 生产能够预防艾滋病毒形成并针对艾滋病毒的疫苗的合理步骤 脑库。