Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells
Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells
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DOI：
10.1093/cid/ciy1066
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发表时间：
2019-10-15
影响因子：
11.8
通讯作者：
Swanstrom, Ronald
中科院分区：
文献类型：
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作者：
Joseph, Sarah B.;Kincer, Laura P.;Swanstrom, Ronald
背景资料。人类免疫缺陷病毒1型(HIV-1)群体在一些接受抑制性抗逆转录病毒治疗(ART)的患者的脑脊液(CSF)中被检测到。对这些人群的详细分析可能会揭示他们是否由中枢神经系统(CNS)储存库产生。我们对101名无症状的参与者进行了一项关于稳定ART的研究。横断面测定脑脊液和血浆中HIV-1RNA浓度。在脑脊液HIV-1 RNA浓度足以进行分析的参与者中，病毒群体在多个时间点上具有遗传和表型特征。对于6%的参与者(6/101)，他们脑脊液中的HIV-1RNA浓度比血浆中的浓度(即脑脊液逃逸)高出0.5个对数拷贝/毫升。我们从3名参与者的脑脊液中生成了病毒包膜序列。一种是持续的脑脊液逃逸群体，它是亲巨噬细胞的，部分耐药，遗传多样性，并与病毒抑制前血液中存在的少量亲巨噬细胞血统密切相关，并在抗逆转录病毒治疗后得到丰富。两名参与者(1名被抑制，1名未被抑制)有短暂的脑脊液逃逸群体，这些群体是R5T细胞嗜性的，遗传多样性很小。对1名参与者的病毒群体的广泛分析显示，脑脊液逃逸来自持续复制的群体，很可能是存在于中枢神经系统的巨噬细胞/小胶质细胞，超过3年的ART。另外两名参与者的脑脊液逃逸可能是由于受感染的T细胞在中枢神经系统内的贩运和短暂扩张造成的。我们的结果表明，在抗逆转录病毒治疗期间，中枢神经系统储备库可以持续存在，而脑脊液逃逸并不完全是由复制的中枢神经系统储存库产生的。
Background. Human immunodeficiency virus type 1 (HIV-1) populations are detected in cerebrospinal fluid (CSF) of some people on suppressive antiretroviral therapy (ART). Detailed analysis of these populations may reveal whether they are produced by central nervous system (CNS) reservoirs.Methods. We performed a study of 101 asymptomatic participants on stable ART. HIV-1 RNA concentrations were cross-sectionally measured in CSF and plasma. In participants with CSF HIV-1 RNA concentrations sufficient for analysis, viral populations were genetically and phenotypically characterized over multiple time points.Results. For 6% of participants (6 of 101), the concentration of HIV-1 RNA in their CSF was >= 0.5 log copies/mL above that of plasma (ie, CSF escape). We generated viral envelope sequences from CSF of 3 participants. One had a persistent CSF escape population that was macrophage-tropic, partially drug resistant, genetically diverse, and closely related to a minor macrophage-tropic lineage present in the blood prior to viral suppression and enriched for after ART. Two participants (1 suppressed and 1 not) had transient CSF escape populations that were R5 T cell-tropic with little genetic diversity.Conclusions. Extensive analysis of viral populations in 1 participant revealed that CSF escape was from a persistently replicating population, likely in macrophages/microglia, present in the CNS over 3 years of ART. CSF escape in 2 other participants was likely produced by trafficking and transient expansion of infected T cells in the CNS. Our results show that CNS reservoirs can persist during ART and that CSF escape is not exclusively produced by replicating CNS reservoirs.