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。 该病毒隐藏在各种解剖隔室中，如男性生殖道（MGT），每个隔室在它们的 血管、生理化学和免疫环境以及ART渗透。这些特征塑造了 艾滋病毒适应这些隔间，并可能有相当大的影响，艾滋病毒的治疗策略。的 MGT是一个独特的艾滋病毒避难所，其可访问性使其成为调查艾滋病毒如何持续的主要候选人 并在现代艺术的背景下在解剖组织中传播。 这项建议的目标是确定：1）如果MGT，特别是前列腺，支持传播艾滋病毒 感染的现代ART的设置，2）如果艾滋病毒之间的血液和MGT在ART期间，和3）如何临床 病毒学因素影响MGT中的残留复制。 为了实现这些目标，我们将评估30名在急性感染期间开始ART的HIV感染男性， 病毒学抑制> 96周，并且之前可获得一对血液和精液样本 开始抗逆转录病毒治疗我们将前瞻性采集配对血液、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，前列腺刺激前1例。所有采集间隔>6个月。从这些 样本，我们将：测量低水平的HIV RNA水平，测序全长env HIV DNA群体， 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， ART期间的繁殖（即进化）以及血液和精液之间的迁移。理解相互作用 艾滋病毒与当地环境之间的相互作用是制定艾滋病毒根除战略的先决条件。 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