The Prostate as a Reservoir for Residual Replication

摘要 艾滋病毒与人类免疫系统和抗逆转录病毒疗法(ART)玩着一场复杂的捉迷藏游戏。 病毒隐藏在不同的解剖间隔中，如男性生殖道(MGT)，每个解剖间隔的不同 血管、理化和免疫环境以及抗逆转录病毒药物的渗透。这些功能塑造了 艾滋病毒适应于这些分类，并可能对艾滋病毒治疗战略产生相当大的影响。这个 MGT是一个独特的艾滋病毒庇护所，它的可访问性使其成为研究艾滋病毒如何持续存在的首选 并在现代艺术的背景下在解剖组织中传播。 这项提案的目标是确定：1)MGT，特别是前列腺是否支持传播艾滋病毒 现代ART环境中的感染，2)如果HIV在ART期间在血液和MGT之间传播，以及3)如何临床 病毒学因素影响MGT的残留复制。 为了实现这些目标，我们将评估30名在急性感染期间开始抗逆转录病毒治疗的艾滋病毒感染男性。 病毒学上被抑制了96周，并事先获得了一对血液和精液样本 敬艺术启蒙。我们将前瞻性地收集配对的血液、精液和尿液的3个时间点样本：2个样本 前列腺刺激后1例，未行前列腺刺激1例。每隔6个月收集一次。从这些 样本，我们将：测量低水平的HIV RNA水平，测序全长环境HIV DNA种群，以及 测量临床和病毒学因素。有了这些数据，我们将描述与病毒相关的因素 在ART期间的传播(即进化)以及血液和精液之间的迁移。了解相互影响 艾滋病毒与其当地环境之间的关系是制定根除艾滋病毒战略的先决条件。 1

ABSTRACT HIV plays a complicated game of hide-and-seek with the human immune system and antiretroviral therapy (ART). The virus hides in various anatomic compartments, like male genital tract (MGT), which each differ in their vascular, physiochemical and immunological environments and ART penetration. These features shape how HIV adapts to these compartments, and may have considerable implications for the HIV cure strategies. The MGT is a unique HIV sanctuary and its accessibility makes it a prime candidate for investigating how HIV persists and propagates in anatomic tissues in the setting of modern ART. The goals of this proposal are to determine: 1) if the MGT, and prostate in particular, supports propagating HIV infection in the setting of modern ART, 2) if HIV traffics between blood and MGT during ART, and 3) how clinical and virologic factors influence residual replication in the MGT. To accomplish these goals, we will evaluate 30 HIV-infected men who started ART during acute infection and virologically suppressed for > 96 weeks and for whom one paired blood and semen sample are available prior to ART initiation. We will prospectively collect 3 timepoint sampling of paired blood, semen and urine: 2 samplings after prostate stimulation and 1 without prior prostate stimulation. All collected >6 months apart. From these samples, we will: measure low level HIV RNA levels, sequence full length env HIV DNA populations, and measure clinical and virological factors. With these data, we will characterize the factors associated with viral propagation (i.e. evolution) during ART and migration between blood and semen. Understanding the interplay between HIV and its local environment is a pre-requisite for designing HIV eradication strategies. 1