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

尽管在开发艾滋病毒疫苗方面做出了巨大努力，但目前还没有预防艾滋病毒的疫苗 感染随着抗逆转录病毒疗法的高度成功，与艾滋病毒相关的死亡率和发病率 感染已大大减少。不幸的是，机会性感染通常在 艾滋病毒感染者，仍然是一个必须紧急解决的问题。经常遇到的 艾滋病毒相关的机会性感染是肺孢子虫肺炎（PCP），这是由无处不在的 真菌耶氏肺孢子虫。虽然抗逆转录病毒疗法降低了PCP的发病率，但30%的艾滋病毒感染者- 受感染的个体将发展PCP，尽管目前的药物治疗， 治疗。PCP通常是不知道自己感染HIV的感染患者的一种决定性疾病。目标 这个K 01奖是支持我的研究计划的过渡，以开发新的治疗方法， 机会性感染影响HIV/AIDS患者，并在非人灵长类动物（NHP）中测试这些疗法 艾滋病毒感染模型。我以前的研究主要集中在细菌的结构机制， 发病机制和抗体介导的对病毒病原体的免疫。虽然我在我的工作中非常成功， 以前的培训，我希望额外的保护时间，以过渡我的研究在一个令人兴奋的和独立的 指导研究抗体介导的对影响HIV/AIDS患者的机会性病原体的免疫， 特别是结合NHP，这是HIV感染的最佳模型。为了完成训练，我 利用格鲁吉亚大学NHP核心的优秀资源，我的主要导师凯伦博士 诺里斯最近在她搬到UGA期间成立。本申请中提出的工作将集中在 在HIV感染的NHP模型中开发治疗PCP的治疗性抗体。我的总体假设是 肺孢子虫kexin蛋白酶特异性抗体可以有效治疗PCP。诺里斯博士开发了 HIV/PCP共感染的优秀NHP模型，并确定了基于蛋白质的候选疫苗（KEX 1） 基于肺孢子虫kexin蛋白酶。拟议的工作将结合联合收割机我目前的专业知识，在抗体 在诺里斯博士和我的临床导师艾莉森博士的指导下， 莫里斯在具体目标1中，我将确定KEX 1疫苗接种后产生的抗体是否能有效地 治疗PCP肺孢子虫kexin蛋白的KEX 1片段先前显示出对肺孢子虫的免疫保护作用。 PCP的发展。我将纯化KEX 1特异性抗体，并在NHP中测试用于治疗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， 分离对KEX 1蛋白特异的新型人抗体。将对抗体进行表征以鉴定 最佳候选人，最佳候选人将在NHP模型中测试PCP治疗效果。我预计 最佳候选药物将进入临床试验，并有很大的潜力作为治疗艾滋病毒中PCP的治疗药物- 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.