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，为感染艾滋病毒的患者提供了能够将病毒载量降低到无法检测到的水平的药物鸡尾酒疗法，但这种疗法无法从宿主中消除病毒，导致在停止这种治疗时病毒血症迅速重新出现到治疗前的水平。人们已经投入了大量的努力来了解HIV病毒库的播种和长期维持，然而，它们是复杂的，由于所谓的“避难所”，即使在药物治疗良好的宿主中，残留的复制也很可能得到维持。了解病毒在急性感染期间死灰复现、持续复制和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，用于监测这种病毒过程的工具要么是间接的，要么是非常具有侵入性的，显然在人类临床中不实用。即使使用非人类灵长类动物的艾滋病模型，如果选择连续牺牲，实时了解病毒动态也是具有挑战性的，而且代价高昂，更不用说个体之间存在很大程度的差异。相反，测量单个抗逆转录病毒药物、预防和治疗性疫苗、免疫疗法和其他疗法的有效性将受益于更精确地监测病毒在体内的空间复制，显示药物渗透不良的潜在位点等。显然，开发一种敏感、特异性和非侵入性的方法来监测HIV在人类或非人类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，对抗SIV gp120（一种病毒表面糖蛋白），该造影剂将特异性靶向SIV感染的恒河猴体内的SIV感染细胞和病毒。该试剂将允许对活体猕猴体内受病毒感染的细胞、组织和游离病毒进行全身、非侵入性、定量分析，作为时间和空间的函数。通过该项目的目标，将为造影剂制定最佳剂量和成像方案，将使用标准诊断对成像准确性和灵敏度进行彻底调查，最后，将评估造影剂在抗逆转录病毒治疗期间对感染的空间变化进行成像的能力。

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.