Blocking granzyme-mediated immune suppression to enhance HIV vaccine efficacy

阻断颗粒酶介导的免疫抑制以增强艾滋病毒疫苗的功效

• 批准号: 10673227
• 负责人: Vijayakumar Velu
• 金额: $ 85.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673227
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Cell Death; Cells; Cessation of life; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Dissection; Dose; Enzyme-Linked Immunosorbent Assay; Evaluation; Flow Cytometry; Fostering; Generations; Genes; Goals; Granzyme; HIV; HIV Infections; HIV envelope protein; HIV vaccine; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunization; Immunologics; Immunosuppression; Impairment; In Vitro; Individual; Infection; Infusion procedures; Invaded; Investigation; Killer Cells; Longevity; Macaca; Macaca mulatta; Measurable; Measures; Mediating; Mediator; Modeling; Molecular; Mus; Natural Killer Cells; Outcome Study; Persons; Phase; Population; Prevention; Recording of previous events; Rectum; Research; Role; SIV; Scheme; Structure of germinal center of lymph node; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Toxicity Tests; Vaccination; Vaccines; Viral; Virus; Work; adaptive immune response; adaptive immunity; autoreactivity; cell killing; comorbidity; experimental study; global health; high risk; human model; immunoregulation; improved; in vivo; inhibitor; innovation; neutralizing antibody; next generation; nonhuman primate; novel vaccines; pandemic disease; pathogen; perforin; prevent; public health intervention; receptor; rectal; response; restraint; simian human immunodeficiency virus; small molecule; small molecule inhibitor; success; tool; tumor; vaccine efficacy; vaccine response; vaccine strategy

SUMMARY Immunization represents one of the most successful public health interventions in human history, preventing more than 2 million deaths each year. Vaccine success depends on a variable combination of antibodies that can neutralize the invading pathogen and virus-specific T cells that kill infected targets. However, the induction of neutralizing antibodies and antiviral T cells that are sufficiently functional and broadly targeted to thwart a highly mutable pathogen like HIV has proven exceptionally difficult in both humans and animal models. Thus, there is currently no efficacious vaccine to prevent the nearly 5,000 new infections with HIV that occur each day. This shortcoming in vaccine success is likely due to intrinsic immune regulatory mechanisms that limit the quantity and quality of HIV-specific immune responses. Development of translational means to overcome these immunological roadblocks holds great promise for advancement of next-generation vaccines to prevent HIV infection and improve global health. Our research focuses on the remarkable capacity of natural killer (NK) cells to suppress the magnitude and quality of antiviral T and B cell responses triggered after immunization. NK cells impair the generation of protective neutralizing antibody responses by inhibiting follicular helper T cell responses and restricting affinity maturation of antibodies within germinal centers. This NK-cell immunosuppression also limits the quantity and quality of antiviral memory T cell responses. NK cells achieve this suppressive effect via perforin-dependent killing of activated T cells, although the specific receptors used to recognize target T cells and perforin-delivered granzymes involved in triggering cell death remain incompletely defined. Whereas inhibition of perforin could curtail NK cell-mediated immune suppression, this broad of an approach could temporarily undermine immunity against pathogens and tumors, and thus a more refined approach targeting granzymes is proposed. Therefore, the goal of this proposal is to advance an innovative high risk, high impact approach to foster HIV vaccine efficacy through selective inhibition of granzymes involved in the immunosuppressive activity of NK cells. Initial experiments in mice will use small molecule inhibitors and CRISPR to define the utility of targeting a specific granzyme to limit NK-cell killing of T cells and suppression of vaccine-elicited adaptive immunity. Select inhibitors will be validated in Rhesus macaques. Based on quantitatively defined go/no-go criteria establishing the success of granzyme targeting to enhance vaccine efficacy, we will proceed to evaluation of this approach in vaccine- mediated prevention of SIV infection in non-human primates. These experiments will also open impactful avenues of investigation into the molecular features of both the immunosuppressive subset of NK cells and targeted subpopulation of T cells. Thus, the proposed work will facilitate subsequent development and deployment of innovative strategies to enhance HIV vaccine efficacy.

概括 免疫是人类历史上最成功的公共卫生干预措施之一，阻止 每年有超过200万人死亡。疫苗成功取决于抗体的可变组合 可以中和杀死受感染靶标的入侵病原体和病毒特异性T细胞。但是，归纳 中和抗体和抗病毒T细胞的功能足够功能，广泛针对阻碍A 在人类和动物模型中，像HIV这样的高度可变的病原体都非常困难。因此， 目前尚无有效的疫苗来防止每天发生近5,000种新的艾滋病毒感染。 疫苗成功的这种缺点可能是由于固有的免疫调节机制限制了 HIV特异性免疫反应的数量和质量。转化手段的发展来克服这些 免疫障碍对下一代疫苗的发展有很大的希望，以防止艾滋病毒 感染并改善全球健康。 我们的研究重点是自然杀手（NK）细胞的显着能力来抑制大小和 免疫后触发的抗病毒T和B细胞反应的质量。 NK细胞会损害生成 通过抑制卵泡辅助T细胞反应和限制亲和力，保护性中和抗体反应 生发中心内抗体的成熟。这种NK细胞免疫抑制也限制了数量和 抗病毒记忆T细胞反应的质量。 NK细胞通过依赖穿孔蛋白实现这种抑制作用 杀死活化的T细胞，尽管用于识别靶T细胞和渗透蛋白的特定受体杀死 涉及触发细胞死亡的粒酶仍未完全定义。而抑制穿孔可以 减少NK细胞介导的免疫抑制，这种宽的方法可能会暂时破坏免疫力 提出了针对病原体和肿瘤，因此提出了针对颗粒酶的更精致的方法。 因此，该提案的目的是提高创新的高风险，高影响力来促进艾滋病毒 通过选择性抑制涉及NK细胞免疫抑制活性的粒酶，疫苗功效。 小鼠中的初始实验将使用小分子抑制剂，并将CRISPR定义为靶向特定的实用性 颗粒酶以限制T细胞的NK细胞杀死和抑制疫苗吸收的适应性免疫。选择抑制剂 将在恒河猕猴中进行验证。基于定义定义的GO/NO-GO标准建立成功 颗粒靶靶向增强疫苗功效的靶向，我们将继续评估疫苗的这种方法 介导的非人类灵长类动物中SIV感染的预防。这些实验也将打开影响力 研究NK细胞的免疫抑制子集的分子特征的研究途径和 T细胞的靶向亚群。因此，拟议的工作将促进后续发展，并 部署创新策略以增强HIV疫苗功效。