Therapeutic antibodies to treat Pneumocystis pneumonia in a nonhuman primate model of HIV infection

尽管为开发艾滋病毒疫苗付出了巨大努力，但目前还没有预防艾滋病毒的疫苗 感染。随着非常成功的抗逆转录病毒治疗的到来，与艾滋病毒相关的死亡率和发病率 感染已显著减少。不幸的是，机会性感染在 这对感染艾滋病毒的患者构成威胁，仍然是一个必须紧急解决的问题。一种常见的 HIV相关的机会性感染是肺孢子虫肺炎(PCP)，由无处不在的 真菌吉罗维西肺孢子虫。尽管抗逆转录病毒治疗降低了PCP的发病率，但30%的艾滋病毒- 感染的人会患上PCP，尽管目前有药物，但这种疾病可能会产生不可接受的致命后果 治疗。PCP通常是感染患者的一种决定性疾病，他们并不知道自己感染了艾滋病毒。目标是 是为了支持我的研究计划的过渡，以开发新的治疗方法 影响HIV/AIDS患者的机会性感染，并在非人灵长类动物(NHP)中测试这些疗法 HIV感染的模型。我之前的研究主要集中在细菌的结构机制上 病毒病原体的发病机制和抗体介导的免疫。尽管我在我的事业中取得了很大成功 在之前的培训中，我希望有更多的保护时间来将我的研究转变为令人兴奋和独立的 方向：研究抗体介导的对影响HIV/AIDS患者的条件病原体的免疫， 特别是纳入代表艾滋病毒感染最佳模式的国家卫生政策。为了完成我的训练，我是 利用佐治亚大学NHP核心的优秀资源，我的主要导师凯伦博士 诺里斯最近在搬到UGA期间建立了自己的公司。本应用程序中建议的工作将集中在 NHP HIV感染模型中治疗PCP的治疗性抗体的开发。我的总体假设是 针对肺孢子虫kexin蛋白水解酶的抗体可以有效地治疗PCP。诺里斯博士已经研制出 一种优秀的HIV/PCP混合感染的NHP模型，并已确定了一种基于蛋白质的候选疫苗(KEX1) 以肺孢子虫kexin蛋白酶为基础。拟议的工作将结合我目前在抗体方面的专业知识 在诺里斯博士和我的临床导师艾莉森博士的指导下，在艾滋病毒领域进行了新的培训 莫里斯。在具体目标1中，我将确定在接种KEX1疫苗时产生的抗体是否有效 治疗PCP。肺孢子虫kexin蛋白的KEX1片段先前被证明可以预防 五氯苯酚的发展。我将提纯KEX1特异性抗体并测试用于治疗NHP中PCP的抗体 HIV/PCP混合感染模型。在具体目标2中，我将利用我在人类抗体生成方面的专业知识来 分离针对KEX1蛋白的新的人类抗体。抗体的特征将识别 排名第一的候选人，以及排名第一的候选人将在NHP模式中接受五氯苯酚治疗疗效测试。我期待着 最佳候选者将进入临床试验，并有很高的潜力用于治疗艾滋病毒中的PCP- 被感染的人。

Despite tremendous efforts to develop a HIV vaccine, there is currently no vaccine for the prevention of HIV infection. With the advent of highly successful antiretroviral therapy, mortality and morbidity associated with HIV infection has been significantly reduced. Unfortunately, opportunistic infections are commonly observed among HIV-infected patients, and remain a problematic issue that must be urgently addressed. A frequently encountered HIV-associated opportunistic infection is Pneumocystis pneumonia (PCP), which is caused by the ubiquitous fungus Pneumocystis jirovecii. Although antiretroviral therapy has reduced the incidence of PCP, 30% of HIV- infected individuals will develop PCP, which can have unacceptable lethal outcomes despite current drug treatments. PCP is often a defining disease in infected patients who are unaware of their HIV infection. The goal of this K01 award is to support the transition of my research program to develop new therapeutics for opportunistic infections affecting HIV/AIDS patients, and to test these therapeutics in a nonhuman primate (NHP) model of HIV infection. My previous research has primarily focused on structural mechanisms of bacterial pathogenesis and antibody-mediated immunity to viral pathogens. Although I have been very successful in my previous training, I desire additional protected time to transition my research in an exciting and independent direction to study antibody-mediated immunity to opportunistic pathogens affecting HIV/AIDS patients, particularly incorporating NHPs, which represent the best model of HIV infection. To complete my training, I am leveraging the excellent resources at the University of Georgia NHP core, which my primary mentor Dr. Karen Norris recently established during her move to UGA. The proposed work in this application will focus on the development of therapeutic antibodies to treat PCP in a NHP model of HIV-infection. My overall hypothesis is that antibodies specific to the Pneumocystis kexin protease can effectively treat PCP. Dr. Norris has developed an excellent NHP model of HIV/PCP co-infection, and has identified a protein-based vaccine candidate (KEX1) based on the Pneumocystis kexin protease. The proposed work will combine my current expertise in antibody generation with new training in the HIV field under the guidance of Dr. Norris and my clinical mentor Dr. Alison Morris. In Specific Aim 1 I will determine if antibodies generated in response to KEX1 vaccination can effectively treat PCP. The KEX1 fragment of the Pneumocystis kexin protein was previously shown to protect against development of PCP. I will purify KEX1-specific antibodies and test the antibodies for treatment of PCP in a NHP model of HIV/PCP co-infection. In Specific Aim 2, I will leverage my expertise in human antibody generation to isolate novel human antibodies specific to the KEX1 protein. The antibodies will be characterized to identify the top candidate, and the top candidate will be tested for PCP treatment efficacy in the NHP model. I expect the top candidate will advance to clinical trials, and have high potential to serve as a therapeutic to treat PCP in HIV- infected individuals.