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。项目摘要/摘要 增长年龄和HIV-1感染都与感染频率增加有关，例如 由于肺炎链球菌，以及这些感染的并发症和死亡率更高。 可以使用疫苗来防止许多老年人常见的感染，例如肺炎球菌 肺炎和血流感染。但是，许多老年人，尤其是那些具有潜在的老年人 疾病，患有HIV-1感染的人显示出频率，大小，质量和功能的降低 肺炎球菌疫苗接种后的特定抗体以及临床疫苗衰竭。这些基础 缺陷可能是血液和粘膜部位的感染和疫苗反应的局限性 大多数感染，例如肺炎球菌肺炎，开始。 免疫后，对疫苗的反应迅速开始。我们专注于启动时的不同事件 对针对多糖胶囊的新肺炎球菌疫苗的免疫反应（PCV-13）。 我们研究了T细胞和B细胞反应的初始产生，在血液中暂时鉴定 免疫反映在淋巴生发中心发生的关键早期事件。 T细胞子集，这样 作为T卵泡辅助器和调节细胞（分别为TFH和TFR），促进和调节B细胞 激活和分化，动员并在血液中循环。这些T细胞调节关键蛋白 在B细胞中表达的AID（激活诱导的胞苷脱氨酶）驱动B细胞进行抗体类别 开关重组（CSR）从IgM到IgG和IgA，并通过躯体进行亲和力成熟 超名（SHM）。 SHM增强了这些抗体的亲和力和功能。 TFH和援助活动 在老年人和HIV-1感染的成年人中可能会受到损害，可能导致添加剂免疫 妥协。我们将研究80名成年人，40名，有40名没有HIV-1感染，其中一半是21 - 40年 年龄为55-64岁，以区分两种状态对疫苗反应的完整性的贡献。工作是 在疫苗之前和之后，在两个相关粘膜位点表征抗体水平和质量的独特性 - 在肺炎开始的肺中开始定植的鼻咽，在血液中 侵入性感染从最初的粘膜部位进展，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和力（结合强度）和功能的抗体 （调查性胞毒细胞增多症）。我们表征了这些结果，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的早期反应的影响 由免疫球蛋白基因突变确定的抗体质量的疫苗和分子基础。 通过识别与衰老和HIV-1感染相关的特定缺陷，我们建议指导开发 改善疫苗以更有效地防止这些严重的感染。

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