Dual-Affinity Re-Targeting Proteins for Cure of Newborn Infant HIV-1 Infection

双亲和力重新靶向蛋白治疗新生儿 HIV-1 感染

• 批准号: 9308869
• 负责人: Justin Joseph Pollara
• 金额: $ 15.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308869
• 关键词: Adult; Affinity; Agonist; Antibodies; Autologous; Biological Models; Birth; Bispecific Antibodies; Body Weight; Breast Feeding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Surface Receptors; Cells; Child; Childhood; Clinical Paths; Clinical Trials; Country; Data; Development; Disease Progression; Disease remission; Effector Cell; Evaluation; Event; Foundations; Funding; Goals; Grant; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Infant; Infection; Intervention; Knowledge; Latent Virus; Lead; Life; Malignant Neoplasms; Mediating; Mission; Modeling; National Institute of Child Health and Human Development; Natural Killer Cells; Neonatal; Newborn Infant; Outcome; Passive Immunization; Passive Immunotherapy; Perinatal; Phase; Phenotype; Population; Proteins; Public Health; Recruitment Activity; Regimen; Research; Resources; Safety; Shock; T-Lymphocyte; Testing; Time; Umbilical Cord Blood; United States National Institutes of Health; Vertical Disease Transmission; Viral Load result; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; base; cell killing; clinical development; cost; cytokine; cytotoxic; design; humanized monoclonal antibodies; immunological intervention; improved; innovation; killings; nonhuman primate; novel; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; postnatal; preclinical trial; prevent; transmission process

PROJECT SUMMARY Mother-to-child transmission (MTCT) results in nearly a quarter-million new infant HIV-1 infections each year, mostly occurring in resource limited countries. The long-term goal is to meet the critical need to develop immune interventions to cure infant HIV-1 infection resulting from MTCT. One novel potential strategy is the use of antibody (Ab)-based immunotherapy. Recently developed bispecific Ab-based Dual Affinity Re- Targeting proteins (DARTs) are an innovative type of immunotherapeutic protein capable of recruiting polyclonal adult CD8+ T cells to eliminate HIV-1 infected, and reactivated latently-infected, autologous CD4+ T cells. However, there is a gap in knowledge regarding the ability of DARTs to recruit and redirect newborn infant immune effector cells to target cells infected with HIV-1 virus isolates involved in MTCT. The overall objective of this proposal is to use umbilical cord blood as a model of the naïve newborn immune system to identify DARTs or combinations of DARTs that can recruit neonatal cytolytic effector cells to kill autologous CD4+ T cells infected with infant transmitted/founder virus isolates, and reactivated latent virus. The central hypothesis of this proposal is that DARTs can be used to recruit and redirect polyclonal neonatal CD8+ T cells and natural killer (NK) cells for eradication of cells infected with viruses responsible for MTCT. The specific aims of the proposal are 1) Quantify the ability of HIV-specific DARTs to redirect cord blood CD8+ T cells to kill autologous CD4+ T cells infected with infant T/F virus isolates; 2) Enhance DART-mediated killing of HIV-1 infected cord blood CD4+ T cells; and 3) Quantify the ability of HIV-specific DARTs to eradicate reactivated latently-HIV-infected cells in a cord blood CD4+ T cell latency model. The rationale for the proposed research is that newborn infant infection resulting from perinatal or postnatal MTCT likely represents the most favorable context for successful cure of HIV-1 using passive immunotherapy because cost is mitigated by low infant body weight, and therapy can be initiated within days to weeks of the transmission event; prior to the establishment of large populations latently infected cells. Due to phenotypic and functional differences in effector cell populations present in newborn infants and adults it is crucial to perform evaluation of infant passive immunotherapies with model systems that use cells isolated from umbilical cord blood to recapitulate the effector cells present in newborn infants. In the applicant's opinion the approach is innovative because of the use of novel HIV-specific T cell and NK cell recruiting DARTs, and the development of cord blood model systems to evaluate killing of infected cells and reactivated latently infected cells. The results obtained by completion of the aims of this proposal will be significant because they will demonstrate the efficacy of DARTs for elimination of infant cells infected with HIV-1 T/F virus, and will provide the data needed to support the development of DART-based passive immunization strategies designed to cure infant HIV-infection.

项目摘要 母婴传播每年导致近25万新生儿感染HIV-1， 大多发生在资源有限的国家。长期目标是满足发展的迫切需要， 免疫干预措施，以治愈母婴传播导致的婴儿HIV-1感染。一种新颖的潜在策略是 使用基于抗体（Ab）的免疫疗法。最近开发的双特异性基于Ab的双重亲和重链抗体（Dual Affinity Re-Ab）， 靶向蛋白（DARTs）是一种新型的免疫调节蛋白，能够招募 多克隆成人CD 8 + T细胞消除HIV-1感染，并重新激活潜伏感染的自体CD 4 + T细胞 细胞然而，关于DART招募和重新引导新生儿的能力， 婴儿免疫效应细胞对HIV-1病毒分离株感染的靶细胞参与母婴传播。整体 该提案的目的是使用脐带血作为幼稚新生儿免疫系统的模型， 鉴定可募集新生儿溶细胞效应细胞以杀死自体免疫细胞的DART或DART组合 CD 4 + T细胞感染婴儿传播/创始者病毒分离株，并重新激活潜伏病毒。中央 该提议的假设是DARTs可用于募集和重定向多克隆新生儿CD 8 + T细胞 和自然杀伤（NK）细胞，用于根除感染有导致MTCT的病毒的细胞。具体 该提案的目的是：1）量化HIV特异性DART重定向脐带血CD 8 + T细胞的能力， 感染婴儿T/F病毒分离株的自体CD 4 + T细胞; 2）增强DART介导的HIV-1杀伤 感染的脐带血CD 4 + T细胞;以及3）量化HIV特异性DART根除再活化的CD 4 + T细胞的能力。 在脐带血CD 4 + T细胞潜伏模型中的潜伏HIV感染细胞。拟议研究的理由 由围产期或产后母婴传播引起的新生儿感染可能是最有利的 使用被动免疫疗法成功治愈HIV-1的背景，因为低婴儿体重减轻了成本 体重和治疗可以在传播事件发生后几天到几周内开始;在建立之前 大量潜伏感染的细胞。由于效应细胞的表型和功能差异， 在新生儿和成人中存在的人群中，进行婴儿被动评估至关重要。 使用从脐带血分离的细胞的模型系统的免疫疗法， 存在于新生儿中的效应细胞。申请人认为，该方法是创新的，因为 使用新的HIV特异性T细胞和NK细胞募集DARTs，以及开发脐带血模型 系统来评估感染细胞的杀伤和再活化的潜伏感染细胞。得到的结果 完成这项建议的目标将是非常重要的，因为它们将证明快速反应部队的有效性 用于消除感染HIV-1 T/F病毒的婴儿细胞，并将提供支持 开发基于DART的被动免疫策略，旨在治愈婴儿艾滋病毒感染。