Harnessing NK Memory To Protect Against HIV Infection

利用 NK 记忆来预防 HIV 感染

• 批准号: 9430685
• 负责人: Silke Paust
• 金额: $ 5.86万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9430685
• 关键词: AIDS prevention; ALVAC Vaccine; Adjuvant; Adoptive Transfer; Antibodies; Antibody Response; Antigens; Antiviral Agents; B-Lymphocytes; Binding; Biological Assay; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Cereals; Chemicals; Data; Development; Disease; Dose; Effector Cell; Environment; Flow Cytometry; Formulation; Gastrointestinal tract structure; Gills; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Homing; Human; Immune; Immune Sera; Immune response; Immune system; Immunoglobulin A; Immunoglobulin G; Immunologic Memory; In Vitro; Individual; Infection; Infection prevention; Interferon Type II; Intestines; Liver; Lycopodium plant; Lymphocyte Depletion; Lymphocyte Subset; Lytic; Mediating; Memory; Methods; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Natural Killer Cells; Oral; Ovalbumin; Phenotype; Pollen; Population; Recruitment Activity; Reproduction spores; Risk; Serum; Site; Spleen; Stomach; T-Lymphocyte; Testing; Time; Tissues; Tretinoin; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Viral; Viral Vaccines; antibody-dependent cell cytotoxicity; base; cohort; cytokine; gastrointestinal; humanized mouse; in vivo; intestinal epithelium; killings; lymph nodes; novel; oral vaccine; prevent; public health relevance; response; trafficking; vaccine development; weapons

 DESCRIPTION (provided by applicant): The goal of this proposal is to exploit oral vaccination with a novel HIV envelope (HIVenv)-loaded pollen grain (PG) formulation to elicit a rapid immune response comprising of HIVenv-specific immunological memory in Natural Killer (NK) cells that directly kill HIV infected cells in the gastrointestinal (GI) mucosa, to prevent HIV infection. NK cells are an essential anti-viral weapon of the immune system; they respond quickly to infection, kill infected cells without prior activation, engage multiple targets simultaneously, and secrete large amounts of anti-viral cytokines, such as interferon gamma. Further, NK cells also crosstalk with B cell-mediated Ab- responses through antibody-dependent cell-mediated cytotoxicity (ADCC), a rapid NK cell-mediated lytic function that only requires tagging of target cells by binding Abs that may not even be neutralizing. If these unique NK cell-mediated effector functions could be enhanced through vaccination, and induced rapidly at the site of HIV entry, it may be possible to prevent the establishment of a systemic HIV infection. In support of this postulate, Dr. Paust (PI) and colleagues have recently demonstrated that contrary to conventional paradigm, subsets of NK cells mediate Ag-specific immunological memory to HIV-envelope. However, reliable elicitation of strong mucosal immunity through vaccination remains a challenge. Recently Dr. Gill (Co-I) has pioneered a unique approach that uses pollen grains (PGs) for oral vaccination. PGs, due to their natural toughness, survive the harsh environment of the stomach, and safely ferry antigens (Ags) to the intestine, where they are persorbed cross the intestinal epithelium. Using these methods, we generated data, which show that oral vaccination with ovalbumin (OVA)-loaded lycopodium spores (LS-OVA) results in (i) OVA-specific Abs in serum and fecal matter, (ii) OVA-specific memory NK cells, which degranulate, kill, and mediate ADCC upon in vitro restimulation, and (iii) memory NK cell recruitment to the mucosa upon oral challenge. We further found that HIVenv elicits recall responses in human NK cells in vitro, and in vivo. Based on these considerations, we hypothesize that human NK cells with antiviral activity against HIV represent a potential effector cell population able to prevent systemic HIV infection, and that oral LS-env vaccination elicits HIV-specific memory NK cell responses. We propose to determine the efficacy of a novel oral LS-env vaccine for the induction of long-lived HIV-specific mucosal NK cell-memory responses in humanized mice, and to assess the efficacy of NK cell memory for the prevention of HIV infection. The demonstration of memory NK cells with activity against HIV in human NK cells, and the ability to induce these responses by vaccination would be highly significant, as it would identify a novel adaptive lymphocyte subset that can be targeted by vaccines and directed against HIV.

 描述(由申请人提供)：这项建议的目标是利用一种新型的HIV包膜(HIVenv)负载花粉颗粒(PG)配方的口服疫苗来诱导自然杀伤(NK)细胞中包含HIVenv特异性免疫记忆的快速免疫反应，该免疫记忆直接杀死胃肠道(GI)黏膜中的HIV感染细胞，以防止HIV感染。NK细胞是免疫系统必不可少的抗病毒武器；它们对感染反应迅速，无需事先激活就能杀死受感染的细胞，同时作用于多个靶点，并分泌大量抗病毒细胞因子，如干扰素-γ。此外，NK细胞还通过抗体依赖细胞介导的细胞毒(ADCC)与B细胞介导的抗体反应串扰，ADCC是一种快速的NK细胞介导的裂解功能，只需要通过结合甚至可能不中和的抗体来标记靶细胞。如果这些独特的NK细胞介导的效应功能能够通过疫苗接种得到增强，并在HIV进入部位快速诱导，那么就有可能防止建立系统性的HIV感染。为了支持这一假设，Paust博士(Pi)和他的同事们最近证明，与传统模式相反，NK细胞亚群介导了对HIV包膜的抗原特异性免疫记忆。然而，通过接种疫苗可靠地激发强大的粘膜免疫仍然是一个挑战。最近，吉尔博士(Co-I)开创了一种独特的方法，使用花粉颗粒(PG)进行口服疫苗接种。PGS由于其天然的韧性，可以在恶劣的胃部环境中存活下来，并安全地将抗原(AGS)运送到肠道，在那里它们被吸收穿过肠道上皮。使用这些方法，我们产生的数据表明，口服接种卵蛋白(OVA)负载的石棉孢子(LS-OVA)可导致(I)血清和粪便中的OVA特异性抗体，(Ii)OVA特异性记忆NK细胞，它在体外重新刺激时脱颗粒、杀伤并介导ADCC，以及(Iii)口服攻击时记忆NK细胞重新聚集到粘膜上。我们进一步发现，HIVenv在体外和体内都能在人NK细胞中引起回忆反应。基于这些考虑，我们假设具有抗HIV活性的人NK细胞代表了能够预防系统性HIV感染的潜在效应细胞群，并且口服LS-env疫苗可以引起HIV特异性记忆NK细胞反应。我们建议确定一种新型口服LS-env疫苗在人源化小鼠中诱导长寿的HIV特异性粘膜NK细胞记忆反应的有效性，并评估NK细胞记忆在预防HIV感染中的效果。在人类NK细胞中展示具有抗HIV活性的记忆NK细胞，以及通过疫苗接种诱导这些反应的能力将具有非常重要的意义，因为它将识别出一种新的适应性淋巴细胞亚群，该亚群可以被疫苗靶向并针对HIV。