Immune System Modeling/HIV

总结 最近的多项研究提供了概念证明，即HIV-1感染的“功能性治愈”， 即长期控制艾滋病毒而不继续治疗是可以实现的。VISCONTI研究 确定了14名HIV+患者，他们在HIV-1初期接受了抗逆转录病毒治疗（ART）。 感染，并保持治疗后控制其病毒低于检测限， 停药后中位数89个月。Persaud等人描述了一名感染HIV-1的婴儿， 在出生后30小时内开始ART，在18个月大时停止治疗，然后继续 在病毒反弹前的27个月里，无法检测到，停止治疗。最近的一项研究表明， 接受ART治疗的SIV感染猕猴给予抗整合素α4β7的抗体（Ab）后， 在所有治疗停止后超过9个月未检测到血浆病毒血症。最后，治疗 在一些感染SIV的猕猴中，广泛中和抗体（bnAbs）也导致了病毒学上的 即使在完成Ab治疗后，也可以延长控制时间。 为了实现这些进步的承诺，我们需要更好地了解导致 在没有治疗的情况下建立不可检测或受控的病毒载量。这里我们 我建议开发一套新的模型，以帮助了解功能性治愈是如何 在上述研究中获得的，并了解更普遍的情况下， 条件和干预措施的功能治愈可以实现。为此，我们将与 领先的实验科学家，他们将提供新的数据集，使我们能够实现 具体目标。目标1.确定HIV-1特异性bnAb的作用机制 in vivo.我们将开发新的抗体作用模型， 功能，以解释bnAbs输注在HIV感染者和SIV感染者中的实验。 猕猴这些模型将有助于确定bnAb的主要作用机制。目标2. 确定单克隆抗体治疗是否会导致病毒载量的变化 设定点我们将开发具有多个稳定的病毒载量稳态（高和低）的模型 水平）由免疫反应和建立潜伏的 水库这些模型将通过人类和猕猴的实验数据进行校准 模型的SIV，并将提供一个机制图片的影响，这些抗体。目标3. 确定寨卡病毒感染的宿主内动态，并预测 疗法我们将利用以前的工作目标，为这种新兴的 感染和研究不同疗法的效果，包括抗体，在控制寨卡病毒。

SUMMARY Multiple recent studies have provided proof-of-concept that a “functional cure” of HIV-1 infection, i.e. long-term control of HIV without continued treatment, is achievable. The VISCONTI study identified 14 HIV+ patients, who received antiretroviral treatment (ART) during primary HIV-1 infection, and maintained post-treatment control of their virus below the limit of detection for a median of 89 months after stopping therapy. Persaud et al. described a HIV-1 infected infant who started ART within 30 hours after birth, discontinued therapy at 18 months of age, then remained undetectable, off-therapy, for 27 months before the virus rebounded. A recent study showed that SIV-infected macaques on ART given an antibody (Ab) against the integrin α4β7 could maintain undetectable plasma viremia for over 9 months after all treatment was stopped. Finally, treatment with broadly neutralizing Abs (bnAbs) in some macaques infected with SIV also led to virological control for an extended period even after completion of Ab treatment. To realize the promise of these advances, we need a better understanding of the factors that lead to establishment of undetectable or controlled viral loads in the absence of treatment. Here we propose to develop a set of new models to help understand how functional cure was obtained in the studies mentioned above and to understand more generally under what conditions and interventions functional cure can be achieved. To this end, we will collaborate with leading experimental scientists, who will provide novel datasets that will allow us to fulfil the following specific aims. Aim 1. Determine the mechanisms of action of HIV-1 specific bnAbs in vivo. We will develop new models of antibody action, incorporating multiple biological functions, to explain experiments of bnAbs infusions in HIV-infected humans and SIV-infected macaques. These models will help determine the main mechanisms of action of bnAbs. Aim 2. Determine whether treatment with monoclonal antibodies can lead to a change in viral load set-point. We will develop models with multiple stable steady states of viral load (high and low levels) driven by the interplay between immune responses and the establishment of the latent reservoir. These models will be calibrated by experimental data in humans and in the macaque model of SIV and will provide a mechanistic picture of the effects of these antibodies. Aim 3. Determine the within host dynamics of Zika virus infection and predict the effects of therapy. We will leverage the work in the previous aims to develop models for this emerging infection and study the effects of different therapies, including antibodies, in controlling Zika virus.