The role of non-broadly neutralizing antibodies targeting gp41 structural epitopes in long term nonprogression of HIV infection

靶向 gp41 结构表位的非广泛中和抗体在 HIV 感染长期不进展中的作用

• 批准号: 9140860
• 负责人: Mark Daniel Hicar
• 金额: $ 39.19万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-16 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140860
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antibodies; Antibody Response; Antigen Targeting; Antigens; B-Lymphocytes; Binding; Biological Assay; Biological Models; Caring; Cell Therapy; Clinic; Clinical Data; Collaborations; Complex; Data; Development; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Epitopes; Future; HIV; HIV Antibodies; HIV Antigens; HIV Infections; HIV therapy; Individual; Infection; Infusion procedures; Knowledge; Life; Macaca; Masks; Measures; Methods; Modeling; Mutate; New York; Pilot Projects; Play; Prevalence; Reagent; Recruitment Activity; Role; Sampling; Serum; Specificity; Structure; Surface; Surface Plasmon Resonance; Testing; Therapeutic; Vaccine Design; Vaccines; Viral; Viremia; antibody-dependent cell cytotoxicity; antigen binding; arm; base; cohort; env Gene Products; immune function; immunogenic; immunogenicity; neutralizing antibody; novel; passive antibodies; premature; public health relevance; research study; response; simian human immunodeficiency virus; success; therapeutic vaccine; vaccine candidate; vaccine trial

 DESCRIPTION (provided by applicant): Of the 35 million living with HIV in the world today, small percentages have never received therapy but retain adequate CD4 help and resist progression to AIDS. To date, the immunological constraints leading to this so-called long-term non-progression (LTNP) state remain largely unknown. Certain non-neutralizing antibodies (Abs) have shown protection and control in HIV challenge model systems and the non-neutralizing antibody-dependent cell-cytotoxicity function is thought to play a role in protection seen in the recent RV144 vaccine `Thai Trial'.We have previously isolated a number of non-neutralizing Abs from LTNP subjects' B cells that target two non-linear conformational trimer-dependent epitopes in the HIV surface envelope protein gp41. In preliminary studies these epitopes are present on advanced vaccine candidates that replicate the native surface HIV envelope trimer. In preliminary serum competition studies, targeting of these gp41 non-linear conformational trimer dependent epitopes is more prevalent in LTNP subjects; with 50- 75% of LTNP subjects having high Ab titers. We hypothesize that Abs targeting these non-linear conformational trimer dependent epitopes assist in maintaining the LTNP state by functional targeting of native surface envelope structure. To explore rates of epitope targeting in LTNP subjects, we will recruit a larger number (45 minimum in each arm) of LTNP to compare levels to progressing subjects, maintained on therapy, and HIV negative control samples. We have established collaborations at HIV care clinics across New York State. To measure binding of these structurally targeted Abs to a panel of HIV antigens including proposed vaccine constructs, we will recombinantly express a panel of HIV antigens containing gp41 epitopes. This panel will include leading vaccine candidates and mutated forms of antigen to confirm specificity of binding. ELISA based assays, native gel shift assays and surface plasmon resonance will be used to confirm binding and characterize the specificity of targeted antigen. To identify the function of these Abs in assisting the LTNP state, we will test antibody dependent cell cytotoxicity by these Abs. By fully characterizing the non-linear conformational trimer dependent Abs and their targets, we will provide the basis for future immunogenicity studies to test if these epitopes can assist in protection or control.

 在当今世界3500万艾滋病毒感染者中，有一小部分人从未接受过治疗，但保留了足够的CD 4帮助并抵抗艾滋病的进展。迄今为止，导致这种所谓的长期非进展（LTNP）状态的免疫学限制在很大程度上仍然未知。某些非中和抗体（Abs）已经在HIV攻击模型系统中显示出保护和控制作用，并且非中和抗体依赖性细胞毒性功能被认为在最近的RV 144疫苗“Thai Trial”中看到的保护中起作用。HIV表面包膜蛋白gp 41中的依赖性表位。在初步研究中，这些表位存在于复制天然表面HIV包膜三聚体的高级候选疫苗上。在初步血清竞争研究中，这些gp 41非线性构象三聚体依赖性表位的靶向在LTNP受试者中更普遍; 50- 75%的LTNP受试者具有高Ab滴度。我们假设，靶向这些非线性构象三聚体依赖性表位的Ab通过天然表面包膜结构的功能性靶向来帮助维持LTNP状态。为了探索LTNP受试者中的表位靶向率，我们将招募更多数量（每组至少45例）的LTNP，以比较持续治疗的进展受试者和HIV阴性对照样本的水平。我们在纽约州的艾滋病护理诊所建立了合作关系。为了测量这些结构上靶向的Ab与一组HIV抗原（包括提出的疫苗构建体）的结合，我们将重组表达一组含有gp 41表位的HIV抗原。该小组将包括领先的候选疫苗和突变形式的抗原，以确认结合的特异性。将使用基于ELISA的测定、天然凝胶位移测定和表面等离子体共振来确认结合并表征靶抗原的特异性。为了鉴定这些Ab在辅助LTNP状态中的功能，我们将测试这些Ab的抗体依赖性细胞毒性。通过充分表征非线性构象三聚体依赖性Ab及其靶标，我们将为未来的免疫原性研究提供基础，以测试这些表位是否可以帮助保护或控制。