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: 9856943
• 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/9856943
• 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; 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; Lung infections; 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; mucosal site; mucosal vaccine; prevent; protein expression; response; transcription factor; vaccine access; 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。 疫苗可用于预防老年人常见的一些感染，如肺炎球菌 肺炎和血流感染。然而，许多老年人，特别是那些有潜在危险的人， 艾滋病毒感染者和艾滋病毒-1感染者的感染频率、程度、质量和功能都有所下降 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 缺陷可能是对血液和粘膜部位的感染和疫苗的反应的限制，其中 大多数感染，如肺炎球菌肺炎，是开始的。 免疫后开始迅速对疫苗产生反应。我们关注的是 针对多糖荚膜（PCV-13）的新型肺炎球菌疫苗的免疫应答。 我们研究了T细胞和B细胞应答的初始产生，这些应答在注射后7天在血液中瞬时鉴定。 免疫反应的关键早期事件发生在淋巴生发中心。T细胞亚群，例如 作为促进和调节B细胞的T滤泡辅助细胞和调节细胞（分别为TFH和TFR 活化和分化，被动员并在血液中循环。这些T细胞调节一种关键蛋白质 在B细胞中表达，AID（活化诱导的胞苷脱氨酶）驱动B细胞经历抗体类 从IgM到IgG和伊加转换重组（CSR），并通过体细胞 超突变（SHM）。SHM增强这些抗体的亲合力和功能。过渡联邦政府和国际援助署的活动 可能在老年人和HIV-1感染者中受到损害，可能导致附加免疫 妥协我们将研究80名成年人，其中40名有HIV-1感染，40名没有HIV-1感染，其中一半是21-40岁的成年人。 年龄，55-64岁的一半，以区分两个国家对疫苗反应完整性的贡献。这项工作是 在表征疫苗接种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， 在鼻咽中开始定植，在肺中开始肺炎，在血液中开始定植， 侵袭性感染从最初的粘膜部位发展，因此有效的粘膜防御对于保护至关重要。 接种疫苗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，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应答的影响 抗体质量的分子基础是由免疫球蛋白基因突变决定的。 通过识别与衰老和HIV-1感染相关的特定缺陷，我们建议指导发展 改进疫苗以更有效地预防这些严重的感染。

项目成果

Effective B cell activation in vitro during viremic HIV-1 infection with surrogate T cell stimulation.

通过替代 T 细胞刺激，在病毒血症 HIV-1 感染期间体外有效激活 B 细胞。

• DOI: 10.1016/j.imbio.2018.08.007
• 发表时间: 2018
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Nicholson,LindsayK;Pratap,Harsh;Bowers,Elisabeth;Gunzburger,Elise;Bandi,SrinivasaR;Gardner,EdwardM;Palmer,BrentE;Wright,Timothy;Kittelson,John;Janoff,EdwardN
• 通讯作者: Janoff,EdwardN

Impact of HIV-1 Infection and Antigen Class on T Follicular Helper Cell Responses to Pneumococcal Polysaccharide-Protein Conjugate Vaccine-13.

HIV-1 感染和抗原类别对滤泡辅助 T 细胞对肺炎球菌多糖蛋白缀合疫苗 13 反应的影响。

• DOI: 10.4049/jimmunol.2001133
• 发表时间: 2021
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Jha,Vibha;Nicholson,LindsayK;Gardner,EdwardM;Rahkola,JeremyT;Pratap,Harsh;Scott,James;Borgeson,Mandy;Jacobelli,Jordan;Janoff,EdwardN
• 通讯作者: Janoff,EdwardN