Effects of CSF1R Blockade on Repopulation of SIV Reservoirs from the CNS to the Periphery After Antiretroviral Therapy Interruption

摘要 尽管有效的抗逆转录病毒疗法（ART）可以将HIV维持在血浆中不可检测的水平，但HIV并不 被消灭了当个体停止抗逆转录病毒治疗时，或在病毒短暂发作期间，CNS病毒储库可迅速反弹。我们 和其他人已经发现CNS血管周围巨噬细胞（PVM）群体作为主要靶点发挥作用， 对于CNS中的HIV和SIV感染，以及ART持续存在的病毒储库。注射 的超顺磁性氧化铁纳米颗粒（SPION）证明PVM在CNS内吸收SPION， 随着SIV感染而积累，并从CNS中运输出来，在颈部引流淋巴结中发现 （cLN）、背根神经节、脾脏和骨髓。重要的是，SPION标记的CD 163+巨噬细胞在 SIV-p27免疫反应性证实了SIV可有效感染cLN。这是我们的整体 假设CNS中可识别的PVM群体作为HIV反弹的细胞储存库发挥作用 和SIV在ART期间，和ART停止后，这些细胞可以离开CNS与病毒， 为外围重新播种。为了验证我们的假设，我们建议使用CNS渗透集落刺激因子1 受体（CSF 1 R）抑制剂（BLZ 945）可早期（ART后3个月）消融这些重新接种的CNS PVM 开始）和晚期（ART开始后5个月 停止抗逆转录病毒疗法我们建议使用2种不同的荧光标记SPION， 在早期和晚期BLZ 945治疗之前，以定义驻留和重新填充的PVM的作用 作为SIV的病毒储存库，并阻止它们携带病毒迁移的能力。我们建议用两个假设来检验我们的假设。 具体目标：目标1将确定CSF 1 R阻断可在多大程度上根除脑中的SIV，并阻断脑中的SIV。 在ART存在下，病毒从CNS向外周的免疫依赖性再接种; Aim 2将 确定CSF 1 R阻断是否可以防止脑中SIV储库的再激活和SIV的再增殖。 ART中断后病毒从CNS向外周转移。

Abstract Despite effective anti-retroviral therapy (ART) that maintains HIV at non-detectable levels in plasma, HIV is not eradicated. When individuals are off ART, or during viral blips, CNS viral reservoirs can quickly rebound. We and others have found that a population of CNS perivascular macrophages (PVMs) function as a major target for HIV and SIV infection in the CNS, and the viral reservoir that persists with ART. Intracisternal (i.c.) injection of superparamagnetic iron oxide nanoparticles (SPIONs) demonstrate PVMs take up SPIONs within the CNS, accumulate with SIV infection, and traffic out of the CNS where they are found in cervical draining lymph nodes (cLNs), dorsal root ganglia, spleen, and bone marrow. Importantly, SPION-labeled CD163+ macrophages in the cLN can be productively infected with SIV as evidenced by SIV-p27 immunoreactivity. It is our overall hypothesis that an identifiable population of PVMs in the CNS functions as a cellular reservoir of rebound HIV and SIV during ART, and after ART cessation, and these cells can leave the CNS with virus that potentially reseeds the periphery. To test our hypothesis, we propose to use a CNS-penetrant colony-stimulating factor 1 receptor (CSF1R) inhibitor (BLZ945) that ablates these reservoir-reseeding CNS PVM early (3 months after ART initiation) and late (5 months after ART initiation) during ART in virally suppressed macaques, and in animals undergoing ART cessation. We propose to use 2 different fluorescently tagged SPIONs, injected intra-CSF just prior to early and late BLZ945 treatments, in order to define the role of resident and repopulated PVMs to function as a viral reservoir of SIV, and block their ability emigrate with virus. We propose to test our hypothesis with two Specific Aims: Aim 1 will determine the extent to which CSF1R blockade can eradicate SIV in the brain and block lymphatic-dependent reseeding of virus from the CNS to the periphery in the presence of ART; and Aim 2 will determine whether CSF1R blockade can prevent reactivation of SIV reservoirs in the brain and repopulation of viral reservoirs from the CNS to the periphery after ART interruption.