L'Honneur Anne Sophie, Pipoli Da Fonseca Juliana, Cokelaer Thomas, Rozenberg Flore
Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Unité Mixte de Recherche 8104, Paris, France.
Service de Virologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
J Infect Dis. 2022 Sep 28;226(7):1151-1161. doi: 10.1093/infdis/jiab639.
JC polyomavirus (JCV) mostly causes asymptomatic persistent renal infections but may give rise in immunosuppressed patients to neurotropic variants that replicate in the brain, causing progressive multifocal leukoencephalopathy (PML). Rearrangements in the JCV genome regulator noncoding control region (NCCR) and missense mutations in the viral capsid VP1 gene differentiate neurotropic variants from virus excreted in urine.
To investigate intrahost emergence of JCV neurotropic populations in PML, we deep sequenced JCV whole genome recovered from cerebrospinal fluid (CSF) and urine samples from 32 human immunodeficiency virus (HIV)-infected and non-HIV-infected PML patients at the single-molecule level.
JCV strains distributed among 6 of 7 known genotypes. Common patterns of NCCR rearrangements included an initial deletion mostly located in a short 10-nucleotide sequence, followed by duplications/insertions. Multiple NCCR variants present in individual CSF samples shared at least 1 rearrangement, suggesting they stemmed from a unique viral population. NCCR variants independently acquired single or double PML-specific adaptive VP1 mutations. NCCR variants recovered from urine and CSF displayed opposite deletion or duplication patterns in binding sites for transcription factors.
Long-read deep sequencing shed light on emergence of neurotropic JCV populations in PML.
JC多瘤病毒（JCV）大多引起无症状的持续性肾脏感染，但在免疫抑制患者中可能产生嗜神经毒株，它们在大脑中复制，导致进行性多灶性白质脑病（PML）。JCV基因组调节非编码控制区（NCCR）的重排以及病毒衣壳VP1基因的错义突变可将嗜神经毒株与尿液中排出的病毒区分开来。
为了研究PML中JCV嗜神经毒株群体在宿主体内的出现情况，我们对从32例人类免疫缺陷病毒（HIV）感染和未感染HIV的PML患者的脑脊液（CSF）和尿液样本中回收的JCV全基因组进行了单分子水平的深度测序。
JCV毒株分布于7种已知基因型中的6种。NCCR重排的常见模式包括最初多位于一段短的10个核苷酸序列中的缺失，随后是重复/插入。单个脑脊液样本中存在的多个NCCR变体至少共享1种重排，表明它们源自独特的病毒群体。NCCR变体独立获得了单个或双重PML特异性适应性VP1突变。从尿液和脑脊液中回收的NCCR变体在转录因子结合位点显示出相反的缺失或重复模式。
长读长深度测序揭示了PML中嗜神经JCV毒株群体的出现情况。
