Harnessing NK Memory To Protect Against HIV Infection

利用 NK 记忆来预防 HIV 感染

基本信息

批准号：
8996549
负责人：
Silke Paust
金额：
$ 56.89万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/8996549
关键词：
AIDS prevention ALVAC Adjuvant Adoptive Transfer Antibodies Antibody Response Antigens Antiviral Agents B-Lymphocytes Binding Biological Assay Blood Bone Marrow CD4 Positive T Lymphocytes Cells Cereals Data Development Disease Dose Effector Cell Environment Figs - dietary Flow Cytometry Formulation Gastrointestinal tract structure Gills Goals HIV HIV Envelope Protein gp120 HIV Infections HIV vaccine HIV-1 Health Homing Human Immune Immune Sera Immune response Immune system Immunoglobulin A Immunologic Memory In Vitro Individual Infection Interferon Type II Intestines Life 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 Prevention Reproduction spores Risk Serum Site Spleen Stomach T-Cell Depletion 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 response trafficking vaccine development weapons

项目摘要

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.

DESCRIPTION (provided by application): The goal of this proposal is to exploit oral vaccine with a novel HIV envelope (HIVenv)-loaded pollen grain (PG) formulating to elicit a rapid immunoresponse compliant of HIV-specific immunological memory in Natural Killer (NK) cells that directly kill HIV infected cells in the gastrointestinal (GI) mucosa, to prevent HIV infection. NK细胞是免疫系统的必不可少的抗病毒武器；他们对感染的反应迅速，杀死感染的细胞而没有事先激活，简单地接合多个靶标，并秘密大量的抗病毒细胞因子，例如干扰素伽玛。此外，NK细胞还通过抗体依赖性细胞介导的细胞毒性（ADCC）与B细胞介导的扩散串扰，这是一种快速的NK细胞介导的裂解功能，仅需要通过结合ABS来标记靶细胞，甚至可能不会中和。如果这些独特的NK细胞介导的效应子功能可以通过疫苗增强，并在HIV进入部位迅速诱导，则可能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）及其同事最近证明，与常规范式相比，NK细胞的子集将Ag特异性免疫记忆介导HIV-Envelope。但是，通过疫苗可靠促进强粘膜免疫仍然是一个挑战。最近，吉尔（Gill）博士（Co-I）开创了一种独特的方法，该方法使用花粉颗粒（PGS）进行口服疫苗。 PG由于其自然韧性，可以在摊位的有害环境中生存，并安全地将抗原（AGS）渡轮到肠道上，在那里它们被持久穿过肠上皮。使用这些方法，我们生成了数据，这些数据表明，用椭圆蛋白（OVA）负载的溶血孢子孢子（LS-OVA）导致（I）在血清和粪便中的OVA特异性ABS，（II）ova特异性记忆NK细胞，从而在（II）杀死胞分的II中，杀死和Mudiate Restimiatimine nk ink ycimed nk nk nk s ova spores（ls-ova），从口服挑战的粘膜。我们进一步发现，Hivenv在体外和体内引起人类NK细胞中的回忆。根据这些考虑，我们假设具有抗病毒活性的人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疫苗会引起HIV特异性记忆NK细胞反应。我们建议确定新型口服LS-ENV疫苗在人源性小鼠中诱导长寿命的HIV特异性粘膜NK细胞内存反应的有效性，并评估NK细胞记忆对预防HIV感染的有效性。记忆NK细胞在人类NK细胞中具有针对HIV的活性的记忆NK细胞，以及通过疫苗诱导这些反应的能力将非常重要，因为它将确定一种新型的适应性淋巴细胞亚群，可以由疫苗靶向并针对HIV。