Determining the impact of ultra-small SIV reservoirs on sustained ART-free remission

摘要/摘要 相当大的努力致力于开发艾滋病毒治愈方案，以减少病毒储备库并增强 抗病毒免疫。这些干预措施寻求允许艾滋病毒携带者停止抗逆转录病毒治疗并持续控制 艾滋病毒，导致持续的无抗逆转录病毒治疗缓解。然而，抗逆转录病毒疗法的病毒学和免疫学决定因素- 人们对自由缓解知之甚少。因此，艾滋病毒治疗研究的一个持久问题是如何 FAR干预必须减少病毒库，以获得临床上相关的无ART缓解期。这是一个 艾滋病毒研究界的共同假设是，抗逆转录病毒疗法终止时艾滋病毒储存库的大小 影响病毒反弹时间和抗病毒免疫反应控制病毒的能力 复制。然而，水库大小和Ttr之间的联系尚不清楚，而 治疗后病毒控制(PTC)尚不清楚。然而，解决这些基本问题是具有挑战性的 由于患者组的变异性和难以量化极小的数量，人类临床试验中的问题 体内的病毒库。因此，已经开发了数学模型来预测PTC和TTR后 停止艺术。这些模型预测，病毒库肯定潜伏着成百上千的艾滋病毒。 被感染的细胞将病毒反弹推迟几个月，而潜在宿主的大小决定了 在停止抗逆转录病毒疗法后，抗病毒免疫反应可以控制艾滋病毒的复制。然而，验证这些 对威斯康星医院的预测具有挑战性。 因此，为了实证检验这些预测，我们将使用猴免疫缺陷病毒(SIV)/恒河猴 模型可以精确地设定体内潜伏油藏的大小。为此，我们将把定义数量的 体外自体产生的SIV潜伏感染细胞进入经过ART治疗的SIV幼稚恒河猴。 此外，我们将通过以下方式确定停止ART后重新激活的潜伏感染细胞的数量 建立带有基因条形码SIV的水库。因此，我们将使用这个新的延迟模型来 确定在存在或不存在以下情况下，逐渐变小的SIV储油池对TTR和PTC的影响 抗病毒免疫。 具体目标1：确定已确定的SIV病毒库的TTR。为了实现这一目标，我们将确定TTR值 对于包含5E4、1E4、1E3和1E2潜伏感染细胞的病毒库。 具体目标2：确定病毒库大小和抗病毒免疫对TTR和PTC的影响。在……里面 为此，我们将用编码近全长SIV的重组大鼠流感病毒诱导抗病毒免疫。 确定包含5E4和1E3潜伏感染细胞的水库在抗逆转录病毒治疗后的TTR值和病毒载量。

Abstract/Summary Considerable efforted is devoted to developing HIV cure regimens that reduce viral reservoirs and boost antiviral immunity. These interventions seek to permit people with HIV (PWH) to stop ART and durably control HIV, inducing sustained ART-free remission. However, the virologic and immunologic determinants of ART- free remission are poorly understood. Therefore, one of the enduring questions for HIV cure research is how far interventions must reduce viral reservoirs to attain clinically relevant periods of ART-free remission. It is a common assumption among the HIV research community that the size of HIV reservoirs at ART termination affects the time to viral rebound (TTR) and the capacity of antiviral immune responses to control virus replication. Yet, the association between reservoir size and TTR is unknown, and the immunologic basis of post-treatment viral control (PTC) is unclear. Nevertheless, it is challenging to address these fundamental questions in human clinical trials due to variability in patient groups and difficulty quantifying extremely small viral reservoirs in vivo. As a result, mathematical models have been developed to forecast PTC and TTR after stopping ART. These models predict that viral reservoirs must contain hundreds to thousands of HIV latently infected cells to delay viral rebound for a few months, and the size of latent reservoirs dictates whether antiviral immune responses can control HIV replication after stopping ART. However, validating these predictions in PWH is challenging. Thus, to empirically test these predictions, we will use a simian immunodeficiency virus (SIV)/rhesus macaque model to precisely set the size of latent reservoirs in vivo. To do so, we will infuse defined numbers of autologous in vitro generated SIV latently infected cells into ART-treated, SIV-naïve rhesus macaques. Further, we will determine the number of latently infected cells that reactivate after stopping ART by establishing reservoirs with genetically barcoded SIV. Therefore, we will use this novel latency model to determine how progressively smaller SIV reservoirs affect TTR and PTC in the presence or absence of antiviral immunity. Specific Aim 1: Determine the TTR for defined SIV viral reservoirs. In this Aim, we will determine the TTR for viral reservoirs containing 5e4, 1e4, 1e3, and 1e2 latently infected cells. Specific Aim 2: Determine the impact of viral reservoir size and antiviral immunity on TTR and PTC. In this Aim, we will induce antiviral immunity with recombinant rhadinovirus encoding near full-length SIV and determine the TTR and viral loads post-ART for reservoirs containing 5e4 and 1e3 latently infected cells.