Development of a non-invasive whole body contrast agent for virus detection

描述（由申请人提供）：尽管抗逆转录病毒疗法在过去十年中取得了相当大的进展，为HIV感染患者提供了能够将病毒载量降低至不可检测水平的药物混合物，但这种疗法无法从宿主中消除病毒，导致当这种治疗停止时，病毒血症迅速重新出现至治疗前水平。已经投入了相当大的努力来理解HIV病毒储库的播种和长期维持，然而，它们是复杂的，并且由于所谓的“庇护所”，即使在药物治疗良好的宿主中也可能维持残余复制。了解病毒复活，连续复制以及急性感染期间的初始传播的空间动力学，可以提供新的潜在治疗和疫苗机会。然而，可用于监测这种病毒过程的工具是间接的或非常侵入性的，并且显然在人类临床中不实用。即使使用非人灵长类动物的艾滋病模型，如果选择使用连续的牺牲，了解真实的时间内的病毒动力学也是具有挑战性的，而且成本高得令人望而却步，更不用说个体之间存在很大程度的变异性了。相反，测量单个抗逆转录病毒药物、预防性和治疗性疫苗、免疫疗法和其他疗法的有效性将受益于更精确地监测体内空间病毒复制，显示药物渗透不良的潜在位点等。一种特异性和非侵入性的方法来监测HIV在人类中或SIV在非人灵长类动物中的动态和传播将是非常有益的。因此，本项目的目标是开发一种完全有效的基于免疫球蛋白的正电子发射断层扫描（PET）造影剂，用于对抗SIV gp120（一种病毒表面糖蛋白），该造影剂将特异性靶向SIV感染恒河猴中的SIV感染细胞和病毒。该试剂将允许在活猕猴中作为时间和空间的函数对病毒感染的细胞、组织和游离病毒进行全身、非侵入性、定量询问。通过本项目的目标，将开发造影剂的优化剂量和成像方案，将使用标准诊断进行成像准确性和灵敏度的彻底调查，最后，将进行抗逆转录病毒治疗期间成像剂对感染空间变化成像的能力评价。 公共卫生相关性：目前，可用于监测活体中病毒感染的工具不能真实的表征体内的病毒动力学。为了提供这些信息，我们建议开发一种完全有效的免疫球蛋白为基础的正电子发射断层扫描（PET）造影剂对猴免疫缺陷病毒（SIV）gp120，病毒表面糖蛋白存在于SIV感染的细胞和病毒在活的SIV感染的恒河猴，HIV感染的人的模型。当与计算机断层扫描（CT）相结合时，这种全身成像技术将导致病毒复制，病毒复活，病毒对抗逆转录病毒治疗的反应以及急性感染期间的初始传播的前所未有的观点，这可能提供新的潜在治疗和疫苗监测机会。

DESCRIPTION (provided by applicant): Although antiretroviral therapies have made considerable progress during the past decade, providing HIV infected patients with drug cocktails able to lower viral loads to undetectable levels, such therapy is unable to eliminate the virus from the host leading to a rapid reemergence of viremia to pre-treatment levels when such treatment is discontinued. Considerable efforts have been devoted to understand the seeding and long-term maintenance of HIV viral reservoirs, however, they are complex, and it is likely that residual replication is maintained in even well medicated hosts thanks to so called "sanctuaries". Understanding the spatial dynamics for virus resurgence, continuous replication, as well as the initial dissemination during acute infection, could provide novel potential therapeutic and vaccine opportunities. However, the tools available to monitor such viral processes are either indirect or very invasive and clearly not practical in the human clinic. Even when one uses the nonhuman primate model of AIDS, understanding the viral dynamics in real time is challenging and prohibitively expensive if one chooses to use serial sacrifices, not to mention fraught by a great degree of variability between individuals. Conversely, measuring the effectiveness of individual antiretroviral drugs, preventive and therapeutic vaccines, immunotherapies and other therapies would benefit from a more precise monitoring of spatial viral replication in vivo, showing potential sites of poor drug penetration etc. Clearly, the development of a sensitive, specific and non invasive method for monitoring the dynamics and dissemination of HIV in humans or SIV in nonhuman primates would be of great benefit. Therefore, the goal of this project is to develop a fully validated immunoglobulin-based positron emission tomography (PET) contrast agent against SIV gp120, a viral surface glycoprotein, which will specifically target SIV infected cells and virus in SIV infected rhesus macaques. This agent will allow for whole body, non-invasive, quantitative interrogation of virally infected cells, tissue, and free virus as a function of time and space in living macaques. Through the aims of this project, an optimized dose and imaging protocol will be developed for the contrast agent, a thorough investigation of imaging accuracy and sensitivity using standard diagnostics will be performed, and last, an evaluation of the imaging agent's ability to image spatial variations in the infection during antiretroviral treatment will be performed. PUBLIC HEALTH RELEVANCE: Currently the tools available to monitor viral infections in living subjects are not capable of characterizing viral dynamics within the body in real time. In order to provide this information, we propose the development of a fully validated immunoglobulin-based positron emission tomography (PET) contrast agent against simian immunodeficiency virus (SIV) gp120, a viral surface glycoprotein present on SIV infected cells and virus in living SIV infected rhesus macaques, a model for HIV infected humans. When combined with computed tomography (CT), this technology for whole body imaging will lead to unprecedented views of virus replication, virus resurgence, virus response to antiretroviral treatment, as well as the initial dissemination during acute infection, which could provide novel potential therapeutic and vaccine monitoring opportunities.