The effect of statins on B cell dysfunction in HIV infection

 描述（由申请方提供）：HIV感染导致B细胞功能的多种缺陷，以及慢性多克隆B细胞活化。HIV相关的B细胞功能障碍导致免疫缺陷（可能包括丧失对疫苗抗原的保护性抗体）和发生B细胞非霍奇金淋巴瘤（NHL）的风险升高。尽管接受高效抗逆转录病毒治疗（HAART）的HIV+患者的B细胞应答有所改善，但B细胞区室通常不会完全恢复正常;与未感染HIV的患者相比，接受HAART的患者可继续显示出B细胞刺激性细胞因子水平升高、高丙种球蛋白血症、记忆B细胞水平降低以及对特定抗原的应答降低。在初步研究中，我们发现，在体外暴露于表达CD 40 L的HIV病毒粒子或EB病毒（EBV）后，静息B细胞暴露于辛伐他汀和/或洛伐他汀导致B细胞活化降低。暴露于这些他汀类药物也减少了从晚期HIV患者中获得的B细胞自发产生IG。多中心AIDS队列研究（MACS）中的初步研究表明，接受HAART的HIV阳性男性中使用他汀类药物与血清细胞因子（IL 10、IL 12、IP 10/CXCL 10）水平降低相关，这些细胞因子已知与B细胞活化和/或炎症相关。这项研究的具体目的是提供概念证明的想法，他汀类药物可能是有用的，在减少HIV感染的B细胞室的残余功能障碍。具体目标是确定：1）他汀类药物如何在体外减弱HIV-或EBV-诱导的B细胞活化，以及在体外通过暴露于LPS和HIV诱导的记忆B细胞凋亡，和2）如果他汀类药物的使用与降低的B超活化、改善的B细胞功能水平相关（抗体产生），以及接受HAART的MACS中HIV+患者的循环记忆B细胞和T滤泡辅助细胞水平的提高。这些研究将提供关于他汀类药物降低HIV感染中B细胞功能障碍的潜力的有价值的新信息，从而可能降低艾滋病淋巴瘤的风险并改善对疫苗的反应，包括HIV治疗性疫苗。如果他汀类药物确实能改善B细胞功能并抑制慢性B细胞活化，那么它们很容易被纳入艾滋病毒感染的治疗方案，因为这些药物安全，价格合理，并且广泛使用。

 DESCRIPTION (provided by applicant): HIV infection results in multiple defects in B cell function, as well as in chronic polyclonal B cell activation. HIV- related B cell dysfunction contributes both to immune deficiency, which may include the loss of protective antibodies to vaccine antigens, and to an elevated risk for developing B cell non-Hodgkin lymphoma (NHL). Although B cell responses improve in HIV+ persons receiving highly active anti-retroviral therapy (HAART), the B cell compartment does not generally return fully to normal; individuals on HAART can continue to show elevated levels of B cell-stimulatory cytokines, hypergammaglobulinema, reduced levels of memory B cells, and reduced responses to specific antigens, when compared to HIV-uninfected persons. In preliminary studies, we saw that exposure of resting B cells to simvastatin and/or lovastatin resulted in decreased B cell activation, after exposure to CD40L-expressing HIV virions, or to the Epstein-Barr virus (EBV) in vitro. Exposure to these statins also reduced the spontaneous production of Ig by B cells obtained from individuals with advanced HIV disease. Pilot studies in the Multicenter AIDS Cohort Study (MACS) have shown that statin use in HIV+ men receiving HAART was associated with decreased serum levels of cytokines (IL10, IL12, IP10/CXCL10) that are known to be associated with B cell activation and/or inflammation. The specific aims of this study are designed to provide proof of concept to the idea that statins might be useful in reducing residual dysfunction in the B cell compartment in HIV infection. The specific aims are to determine: 1) how statins can attenuate HIV- or EBV-induced B cell activation in vitro, and the apoptosis of memory B cells that is induced by exposure to LPS and HIV in vitro, and 2) if statin use is associated with reduced B hyperactivation, improved levels of B cell function (antibody production), and improved levels of circulating memory B cells and T follicular-helper cells in HIV+ persons in the MACS receiving HAART. These studies will provide valuable new information on the potential of statins to reduce B cell dysfunction in HIV infection, which may thereby reduce the risk of AIDS-lymphoma and improve responses to vaccines, including therapeutic vaccines for HIV. If statins do improve B cell function and dampen chronic B cell activation, they could readily be included in treatment regimens for HIV infection, as these drugs are safe, affordable, and are in wide use.