Enhancing B cell maturation and function using bisphosphonates in HIV

项目总结/摘要 艾滋病毒感染者和老年人更容易患上流感的潜在致命并发症 (such如肺炎）和侵袭性肺炎链球菌菌血症和脑膜炎。淋巴细胞相关B细胞 缺陷化合物HIV诱导的B细胞功能障碍，严重损害体液免疫应答， 流感病毒和肺炎球菌。因此，预防流感和肺炎球菌的常规疫苗 建议在这些人群中接种，但对这些疫苗的抗体反应很差且无效。 改善B细胞功能和增强对感染和疫苗接种的体液免疫应答的策略是 因此，需要改善艾滋病毒/艾滋病老龄人口的健康结果。 二膦酸盐（BPs），骨吸收抑制剂，用于治疗骨骼疾病，包括 骨质疏松症，出乎意料地改善了小鼠的体液免疫应答，也增加了小鼠的总IgG水平。 患有佩吉特骨病的人。这表明BPs可以作为B细胞靶向佐剂， 抗体反应，但机制不明。我正在进行的K 01正在试点中利用这一观察结果 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， 对感染和疫苗接种的抗体反应。我们的数据确实表明，ZA显著提高了抗- 免疫接种的艾滋病毒感染者（30-50岁）的甲型流感IgG抗体水平提高32%，而仅 安慰剂组为8%。这种增强抗体反应的机制以及它是否发生在 >50岁的PLWH患者不详。此外，口服BP如阿仑膦酸盐和伊班膦酸盐， 其在临床实践中甚至更广泛地用于增强PLWH的体液免疫，这是未知的。目的 这个R 03项目的目的是更好地了解BP增强抗原的潜在机制， 特异性抗体反应。 我们将利用来自BP治疗和非BP治疗的HIV-和HIV+男性和女性参与者的样本 参加了NHLBI资助的联合队列研究（CCS），以证明BP可增强体液免疫， 通过增强B细胞成熟， 功能这些研究扩展了我正在进行的K 01项目，并增加了必要的机械终点，以产生 强有力的数据支持我未来的R 01申请，调查BP介导的 增强老化PLWH的体液免疫。

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.