Enhancing B cell maturation and function using bisphosphonates in HIV

使用双磷酸盐促进 HIV 中 B 细胞的成熟和功能

• 批准号: 10083521
• 负责人: Kehmia Nubonyin Titanji
• 金额: $ 7.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083521
• 关键词: AIDS population; AIDS/HIV problem; Adjuvant; Age; Age-Years; Aging; Alendronate; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; B-Lymphocytes; BLR1 gene; Bacteremia; Biological Assay; Bone Resorption; Cell Compartmentation; Cell Maturation; Cell physiology; Cell surface; Cells; Clinical; Cohort Studies; Data; Defect; Elderly; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemic; Female; Flow Cytometry; Fright; Functional disorder; Funding; Future; Goals; HIV; HIV Infections; HIV Seronegativity; Health; Helper-Inducer T-Lymphocyte; Hemagglutination; Human; Humoral Immunities; Ibandronate; Immune response; Immune system; Immunize; Immunoglobulin G; Immunologics; Impairment; Individual; Infection; Inflammasome; Influenza; Influenza A virus; Influenza vaccination; Interleukin-4; Mediating; Memory B-Lymphocyte; Meningitis; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Oral; Osteitis Deformans; Osteoporosis; Outcome; Parents; Participant; Pharmaceutical Preparations; Pilot Projects; Pneumonia; Polysaccharides; Population; Production; Rest; Sampling; Serological; Signal Transduction; Streptococcal Infections; Streptococcus pneumoniae; T-Lymphocyte Subsets; TNFSF5 gene; Toll-like receptors; Vaccinated; Vaccination; Vaccines; Viral; Virus; Vulnerable Populations; Zoledronic Acid; age effect; aged; anti-influenza; antiretroviral therapy; bisphosphonate; clinical practice; clinically relevant; cytokine; design; improved; influenzavirus; inhibitor/antagonist; male; mortality; novel strategies; pathogen; peripheral blood; placebo group; response; secondary infection; skeletal disorder

PROJECT SUMMARY/ABSTRACT People living with HIV (PLWH) and the elderly more susceptible to potentially fatal complications from influenza (such as pneumonia) and invasive Streptococcus pneumoniae bacteremia and meningitis. Age-associated B cell defects compound HIV-induced B cell dysfunction to severely compromise humoral immune responses to influenza viruses and pneumococcus. Routine vaccinations against influenza and pneumococcus are therefore recommended in these populations but antibody responses to these vaccinations are poor and ineffective. Strategies to improve B cell function and boost humoral immune responses to infection and vaccination are therefore needed to improve health outcomes for the aging HIV/AIDS population. Bisphosphonates (BPs), inhibitors of bone resorption used in the treatment of skeletal disorders including osteoporosis, unexpectedly improved humoral immune responses in mice and also increased total IgG levels in humans with Paget's disease of bone. This suggests that BPs can act as B cell-targeting adjuvants to boost antibody responses, but the mechanism is unknown. My ongoing K01 is leveraging this observation in a pilot study to investigate if the BP Zoledronic Acid (ZA) can reverse HIV-induced B cell dysfunction and improve antibody responses to infection and vaccination. Our data indeed reveal that ZA significantly boosted anti- influenza A IgG antibody levels in immunized HIV-infected individuals (aged 30-50) by 32%, compared to only 8% in the placebo group. The mechanism underlying this boost in antibody responses and whether it occurs in individuals PLWH >50 years old is unknown. Also, the ability of oral BPs such as Alendronate and Ibandronate, which are even more widely used in clinical practice, to boost humoral immunity in PLWH, is unknown. The aim of this R03 project is to gain a better understanding of the potential mechanisms by which BPs boost antigen- specific antibody responses. We will leverage samples from BP-treated and non-BP-treated HIV- and HIV+ male and female participants enrolled in the NHLBI-funded Combined Cohort Study (CCS) to show that BPs boost humoral immunity to clinically-relevant viral (influenza) and bacterial (pneumococcus) antigens by enhancing B cell maturation and function. These studies extend my ongoing K01 project and add essential mechanistic endpoints to generate robust data in support of my future R01 application investigating the molecular mechanisms of BP-mediated enhanced humoral immunity in aging PLWH.

项目摘要/摘要 患有艾滋病毒（PLWH）和老年人的人更容易受到流感的潜在致命并发症的影响 （例如肺炎）和侵袭性肺炎肺炎菌群和脑膜炎。与年龄相关的B细胞 缺陷化合物HIV引起的B细胞功能障碍，严重损害了对体液的免疫反应 流感病毒和肺炎球菌。因此，针对流感和肺炎球菌的常规疫苗接种是 在这些人群中推荐，但对这些疫苗的抗体反应较差且无效。 改善B细胞功能并增强对感染和疫苗接种的体液免疫反应的策略是 因此，需要改善艾滋病毒/艾滋病人群的健康状况。 双膦酸盐（BPS），用于治疗骨骼疾病的骨吸收抑制剂 骨质疏松症，意外改善小鼠的体液免疫反应，也提高了总IgG水平 患有paget病的人。这表明BP可以充当B细胞靶向佐剂以提升 抗体反应，但该机制尚不清楚。我正在进行的K01正在利用飞行员的观察 研究以研究BP唑来膦酸（ZA）是否可以逆转HIV诱导的B细胞功能障碍并改善 抗体对感染和疫苗接种的反应。我们的数据确实表明，ZA显着增强了抗抗 仅32％ 安慰剂组中有8％。抗体反应中这种提升的基础机制以及它是否发生在 个人PLWH> 50岁是未知的。另外，口服BPS（例如α和iBandronate）的能力， 在临床实践中更广泛使用，以提高PLWH的体液免疫力，这是未知的。目的 在这个R03项目中，是为了更好地理解BPS促进抗原的潜在机制 特定的抗体反应。 我们将利用BP处理和未经BP治疗的HIV和HIV+男性和女性参与者的样本 参加了NHLBI资助的总队列研究（CCS），以表明BPS增强了体液免疫力 通过增强B细胞成熟和 功能。这些研究扩展了我正在进行的K01项目，并添加了基本机械终点以生成 强大的数据支持我未来的R01应用，研究了BP介导的分子机制 衰老PLWH的体液免疫增强。