Impact of HIV-1 and Aging on Mucosal Vaccine Responses

HIV-1 和衰老对粘膜疫苗反应的影响

• 批准号: 9242519
• 负责人: Edward N Janoff
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242519
• 关键词: Acute; Address; Adult; Affect; Affinity; Age; Age-Years; Aging; Antibodies; Antibody Formation; Antibody Response; Architecture; Autoimmune Diseases; Avidity; B-Cell Activation; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Bacteremia; Bacteria; Bacterial Pneumonia; Binding; Blood; CD4 Positive T Lymphocytes; Caring; Cell Maturation; Cells; Cellular biology; Cessation of life; Child; Chronic; Clinical; Conjugate Vaccines; DNA; Defect; Development; Disease; Elderly; Enzymes; Epithelial Cells; Event; Failure; Frequencies; Functional disorder; Gene Mutation; Generations; Genes; HIV; HIV-1; Helper-Inducer T-Lymphocyte; Human; IgA1; IgG1; Immune; Immune response; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulin Variable Region; Immunoglobulin-Secreting Cells; Impairment; Incidence; Infection; Inflammation; Interleukin-6; Lung; Lymphoid; Messenger RNA; MicroRNAs; Molecular; Mucous Membrane; Mutation; Nasopharynx; Nose; Opportunistic Infections; Outcome; Pattern; Persons; Pneumococcal Pneumonia; Pneumococcal vaccine; Pneumonia; Polysaccharides; Population; Prevention; Process; Production; Proteins; Provider; Recruitment Activity; Recurrence; Respiratory Mucosa; Risk; Sepsis; Specificity; Stream; Streptococcus pneumoniae; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Transcript; Vaccination; Vaccine Design; Vaccines; Veterans; Virulence Factors; Work; activation-induced cytidine deaminase; age group; antigen antibody binding; antiretroviral therapy; capsule; differential expression; functional disability; improved; influenza virus vaccine; killings; mucosal site; mucosal vaccine; prevent; protein expression; response; transcription factor; vaccine development; vaccine response

7. Project Summary/Abstract Both advancing age and HIV-1 infection are associated with an increased frequency of infection, such as those due to Streptococcus pneumoniae, and a higher rate of complications and death with these infections. Vaccines are available to prevent a number of infections common in older adults, such as pneumococcal pneumonia and blood stream infection. However, many older adults, particularly those with underlying disease, and persons living with HIV-1 infection show a decreased frequency, magnitude, quality and function of specific antibodies following pneumococcal vaccination, as well as clinical vaccine failure. Underlying these defects may be limitations in responses to infection and vaccines in both blood and at mucosal sites, where most infections, such as pneumococcal pneumonia, begin. Responses to vaccines begin quickly after immunization. We focus on the distinct events at the initiation of immune responses to a newer pneumococcal vaccine directed against the polysaccharide capsule (PCV-13). We study the initial generation of both T cell and B cell responses transiently identified in blood at 7 days after immunization that reflect the key early events occurring in the lymphoid germinal centers. T cell subsets, such as T follicular helper and regulatory cells (TFH and TFR, respectively) that promote and modulate B cell activation and differentiation, are mobilized and circulate in blood. These T cells regulate a key protein expressed in B cells, AID (activation-induced cytidine deaminase) that drives B cells to undergo antibody class switch recombination (CSR) from IgM to IgG and IgA and to undergo affinity maturation by somatic hypermutation (SHM). SHM enhances the avidity and function of these antibodies. Both TFH and AID activity may be compromised in both aging adults and those with HIV-1 infection, potentially causing additive immune compromise. We will study 80 adults, 40 with and 40 without HIV-1 infection, half of whom are 21-40 years of age, half 55-64 to distinguish the contributions of both states to the integrity of vaccine responses. The work is unique in characterizing antibody levels and quality at two relevant mucosal sites before and after vaccine - in the nasopharynx where colonization begins, in the lung where pneumonia begins, and in the blood, where invasive infections progress from initial mucosal sites, so effective mucosal defense is essential for protection. The end point of vaccination is to generate antibodies of high avidity (strength of binding) and function (opsonophagocytosis). We characterize these outcomes, the impact of aging and HIV-1 infection on acute TFH, TFR and AID activation, and their impact on the early response of antibody-secreting cells specific for the vaccine and the molecular basis of antibody quality which is determined by immunoglobulin gene mutations. By identifying the specific defects associated with aging and HIV-1 infection, we propose to direct development of improved vaccines to more effectively prevent these serious infections.

7. 项目总结/摘要 年龄增长和 HIV-1 感染都与感染频率增加有关，例如 由于肺炎链球菌，这些感染的并发症和死亡率较高。 疫苗可预防老年人常见的多种感染，例如肺炎球菌 肺炎和血流感染。然而，许多老年人，特别是那些患有基础疾病的老年人 疾病和 HIV-1 感染者表现出频率、程度、质量和功能下降 肺炎球菌疫苗接种后的特异性抗体以及临床疫苗失败。在这些基础上 缺陷可能是血液和粘膜部位对感染和疫苗反应的限制，其中 大多数感染，例如肺炎球菌肺炎，都是在这种情况下开始的。 免疫后很快就会开始对疫苗产生反应。我们关注启动时的不同事件 针对多糖胶囊（PCV-13）的新型肺炎球菌疫苗的免疫反应。 我们研究了 7 天后血液中瞬时鉴定的 T 细胞和 B 细胞反应的初始产生。 免疫反应反映了淋巴生发中心发生的关键早期事件。 T 细胞亚群，例如 作为促进和调节 B 细胞的滤泡辅助 T 细胞和调节细胞（分别为 TFH 和 TFR） 活化和分化，在血液中动员和循环。这些 T 细胞调节关键蛋白质 在 B 细胞中表达，AID（激活诱导胞苷脱氨酶）驱动 B 细胞进行抗体类别 从 IgM 到 IgG 和 IgA 的转换重组 (CSR)，并通过体细胞进行亲和力成熟 超突变（SHM）。 SHM 增强了这些抗体的亲和力和功能。 TFH 和 AID 活动 老年人和 HIV-1 感染者都可能受到损害，可能导致附加免疫 妥协。我们将研究 80 名成年人，其中 40 名感染 HIV-1，40 名未感染 HIV-1，其中一半年龄在 21-40 岁之间。 年龄，一半为 55-64 岁，以区分两个州对疫苗反应完整性的贡献。工作是 在表征疫苗前后两个相关粘膜部位的抗体水平和质量方面具有独特性 - 鼻咽部是定植开始的地方，肺是肺炎开始定植的地方，血液是定植开始的地方。 侵袭性感染从最初的粘膜部位开始发展，因此有效的粘膜防御对于保护至关重要。 疫苗接种的终点是产生高亲合力（结合强度）和功能的抗体 （调理吞噬作用）。我们描述了这些结果，即衰老和 HIV-1 感染对急性 TFH 的影响， TFR 和 AID 激活，及其对特异性抗体分泌细胞早期反应的影响 疫苗和由免疫球蛋白基因突变决定的抗体质量的分子基础。 通过识别与衰老和 HIV-1 感染相关的具体缺陷，我们建议指导开发 改进疫苗以更有效地预防这些严重感染。