Harnessing NK Memory To Protect Against HIV Infection

利用 NK 记忆来预防 HIV 感染

• 批准号: 9204387
• 负责人: Silke Paust
• 金额: $ 55.89万
• 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/9204387
• 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）：本提案的目标是利用新型 HIV 包膜 (HIVenv) 负载花粉粒 (PG) 制剂进行口服疫苗接种，以引发快速免疫反应，其中包括 Natural Killer 中的 HIVenv 特异性免疫记忆（ NK）细胞直接杀死胃肠道（GI）粘膜中的HIV感染细胞，以预防HIV感染 NK细胞是免疫系统的重要抗病毒武器；它们对感染做出快速反应，无需杀死感染细胞。 NK 细胞还通过抗体依赖性细胞介导的细胞毒性 (ADCC) 与 B 细胞介导的 Ab 反应相互作用。快速 NK 细胞介导的裂解功能，只需要通过结合抗体来标记靶细胞，甚至可能不会中和。如果这些独特的 NK 细胞介导的效应功能可以通过疫苗接种得到增强，并在 HIV 进入部位快速诱导，为了支持这一假设，Paust 博士（PI）同事最近发现，与传统模式相反，NK 细胞亚群介导 HIV 包膜的 Ag 特异性免疫记忆。然而，由于花粉粒 (PG) 是天然的，因此通过疫苗接种可靠地引发强粘膜免疫力仍然是一个挑战。韧性，在胃部的恶劣环境中生存，并将抗原（Ag）安全地运送到肠道，在那里它们被肠上皮吸收。使用这些方法，我们生成了数据，表明口服疫苗接种了负载卵清蛋白（OVA）的疫苗。石松孢子 (LS-OVA) 会产生 (i) 血清和粪便中的 OVA 特异性抗体，(ii) OVA 特异性记忆 NK 细胞，可脱颗粒、杀死、并在体外再刺激时介导 ADCC，以及 (iii) 在口服刺激时记忆 NK 细胞募集到粘膜。我们进一步发现 HIVenv 在体外和体内引起人类 NK 细胞的回忆反应。具有抗 HIV 病毒活性的人类 NK 细胞代表了能够预防全身 HIV 感染的潜在效应细胞群，并且口服 LS-env 疫苗接种可引发 HIV 特异性记忆 NK 细胞反应。 LS-env 疫苗用于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，并评估 NK 细胞记忆预防 HIV 感染的功效。证明记忆 NK 细胞具有抗 HIV 活性。在人类 NK 细胞中，通过疫苗接种诱导这些反应的能力将非常重要，因为它将鉴定出一种新的适应性淋巴细胞亚群，可以作为疫苗的目标并针对 HIV。