ライフサイエンスコーパス: JCV

1 JCV detection by quantitative polymerase chain reaction

2 JCV DNA isolated from postmortem tissue samples identifi

3 JCV DNA levels of <100 copies/ml were seen in 14 (70%) o

4 JCV DNA load is higher in circulating CD34(+) cells and

5 JCV DNA was detected in blood of 12 of 43 (27.9%) and in

6 JCV DNA was detected in the CSF of 2 of 27 (7.4%) natali

7 JCV DNA was not detected in peripheral blood mononuclear

8 JCV effectively propagated in these mice, which indicate

9 JCV infection of host cells is dependent on interactions

10 JCV is a ubiquitous small DNA virus that leads to persis

11 JCV proteins were not detected in the spleen or lymph no

12 JCV sequence variation and rearrangements influence vira

13 JCV VP1 substitutions are acquired intrapatient and migh

14 JCV was excreted more frequently by liver than kidney re

15 JCV-specific CD4(+) T cells were detected ex vivo more f

16 JCV-specific cellular immune response is highly prevalen

17 JCV-specific T-cell responses, mediated by both CD4(+) a

18 Of 27 JCV seronegative patients, 10 (37%) had JCV viruria.

19 We enrolled 43 JCV-seropositive MS patients, including 32 on natalizuma

20 5%) patients, M. tuberculosis in 48 (14.5%), JCV in 20 (6.0%), CMV in 20 (6.0%), VZV in 13 (3.9%), HS

21 GCN should be considered as a JCV CNS manifestation in patients with newly developed,

22 data affirm the importance of 5-HT(2A)R as a JCV receptor and demonstrate that the sialic acid compon

23 erebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst pa

24 lear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response.

25 In addition, JCV DNA was detected in some spleen, lymph node, bone, a

26 arides from the cell surface, did not affect JCV infection in 5-HT(2A)R-expressing cells.

27 he development of novel drugs active against JCV infection.

28 he role of CD4(+) and CD8(+) T-cells against JCV in the clinical outcome of PML and PML in the settin

29 tment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to c

30 ed that the cellular immune response against JCV is associated with better clinical outcome.

31 umoral and cellular immune responses against JCV.

32 r immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

33 f urinary shedding of polyomaviruses BKV and JCV and their relationship to creatinine clearance (CrCl

34 These findings suggest that BKV and JCV display different patterns of reactivation and shedd

35 tes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell

36 Although both LACV and JCV are highly neurovirulent in 21 day-old mice, with 50

37 PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS.

38 entities: JCV granule cell neuronopathy and JCV encephalopathy.

39 alopathy, JCV granule cell neuronopathy, and JCV encephalopathy.

40 talizumab treatment should be suspended, and JCV polymerase chain reaction testing and brain magnetic

41 Anti-JCV antibody index cutoffs were selected via sensitivity

42 Anti-JCV antibody index data were available for serum/plasma

43 Anti-JCV antibody levels in serum/plasma, measured as index,

44 Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays per

45 MS patients, 53.6% tested positive for anti-JCV antibodies, with a 95% confidence interval of 49.9 t

46 ed using a probability distribution for anti-JCV antibody index values, separately for patients with

47 For anti-JCV antibody-negative patients (n=13 996), estimated PML

48 For anti-JCV antibody-positive patients in this pooled cohort, cu

49 allows further risk stratification for anti-JCV antibody-positive patients who have not previously t

50 For anti-JCV antibody-positive patients without previous immunosu

51 PML patients displayed sustained higher anti-JCV antibody index over time.

52 as index, may differentiate PML risk in anti-JCV antibody-positive MS patients with no prior immunosu

53 ody levels and PML risk was examined in anti-JCV antibody-positive multiple sclerosis (MS) patients f

54 In anti-JCV antibody-positive patients (n=21 696), estimated cum

55 Incorporating anti-JCV antibody index allows further risk stratification fo

56 Notably, we observed anti-JCV antibodies in all 17 available pre-PML sera samples,

57 etecting and confirming the presence of anti-JCV antibodies in human serum and plasma was developed a

58 y was used to determine the presence of anti-JCV antibodies in natalizumab-treated PML patients where

59 detectable or not detectable levels of anti-JCV antibodies.

60 d to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index).

61 Continued evaluation of anti-JCV antibody index and PML risk is warranted.

62 lgorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into stand

63 ction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naive pa

64 ing an index below and above a range of anti-JCV antibody index thresholds were calculated using all

65 Longitudinal stability of anti-JCV antibody index was also evaluated.

66 ithout imputation for missing values of anti-JCV antibody status and previous immunosuppressant use.

67 We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immu

68 The association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JC

69 -treated PML patients and 2,522 non-PML anti-JCV antibody-positive patients.

70 trations of anti-JCV antibody in serum (anti-JCV antibody index).

71 Specific anti-JCV antibody was measured in plasma/sera samples from 25

72 research on the clinical utility of the anti-JCV antibody assay as a potential tool for stratifying M

73 Through measurement of the anti-JCV antibody index, and in combination with the presence

74 initiating, natalizumab, based on their anti-JCV antibody status.

75 ts with no prior immunosuppressant use, anti-JCV antibody index distribution was significantly higher

76 Among patients who were anti-JCV antibody negative at baseline in the AFFIRM and STRA

77 We analyzed whether anti-JCV antibody levels, measured as index, may further defi

78 Archetype JCV is present in bone marrow and uroepithelial cells of

79 Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated

80 n 6 to 47 months (mean = 26.1 months) before JCV antibody testing.

81 ogical and immunological differences between JCV Mad-4 and CY.

82 Recombination between JCV and EBV occurs in B lymphoblasts at a sequence essen

83 nd regulatory micro (mi)RNA clusters of BKV, JCV and SV40.

84 y, we detected multiple subtypes of the BKV, JCV and TTV.

85 4(+) T-cell counts and qPCR-determined brain JCV load among patients with HIV infection (r(2) = -0.9;

86 ad was strongly associated with higher brain JCV DNA load (Spearman rho = 0.65; P = .004; n = 18).

87 NPCs can be nonproductively infected by JCV, while infection of progenitor-derived astrocytes (P

88 inflammatory syndrome (IRIS), but in 2 cases JCV persisted > 21 months after IRIS accompanied by dela

89 nd 0.5 log(1)(0) PFU, respectively, chimeric JCV/LACV is highly attenuated and does not cause disease

90 ucial to support CD8(+) T cells in combating JCV infection of the CNS.

91 Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could

92 d with fluorescein isothiocyanate-conjugated JCV demonstrated that JCV enters the B cells, and DNase

93 s to assess the complementary value of a CSF JCV antibody index (AIJCV ) in the diagnosis of natalizu

94 unique opportunity to characterize in detail JCV-specific CD4(+) T cell clones from the infected tiss

95 onfirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who test

96 We detected JCV large T DNA by quantitative PCR of archival brain sa

97 In the same samples, we detected JCV regulatory region DNA by nested PCR in 6/19 (32%) HI

98 od, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immuno

99 to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors.

100 f different strategies to mount an efficient JCV-specific immune response including TCR bias, HLA cro

101 cognition of two distinct clinical entities: JCV granule cell neuronopathy and JCV encephalopathy.

102 Presented is the first case of fatal JCV encephalopathy after immunosuppressive therapy that

103 ns are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid bin

104 Finally, JCV variants can also infect neurons, leading to the rec

105 y fluids (urine and blood) were assessed for JCV DNA by real time quantitative polymerase chain react

106 or natalizumab warrants early assessment for JCV infection.

107 he favorable transcriptional environment for JCV in PDAs.

108 n B lymphoblasts at a sequence essential for JCV neurovirulence and in cerebrospinal fluid of immunos

109 eptors has been reported to be important for JCV infection.

110 hymus, we generated a novel animal model for JCV infection.

111 At time of the first positive qPCR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associ

112 g quantitative polymerase chain reaction for JCV DNA identification.

113 as well as increase in virus replication for JCV, MCV, TSV and HPyV7.

114 -linked glycosylation sites are required for JCV infection.

115 iremic but had seronegative test results for JCV antibodies.

116 and the Exact v1/v2 prototype standards for JCV showed 8-fold and 4-fold variation in genomic covera

117 that astroglial infection is sufficient for JCV spread.

118 indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection

119 natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative poly

120 ebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses

121 ) of LACV is replaced with that derived from JCV and is flanked by the untranslated regions of LACV.

122 This syndrome resulted from JCV granule cell neuronopathy associated with a novel JC

123 PML results from JCV reactivation in the setting of impaired cellular imm

124 Furthermore, JCV-infected glial cells are frequently located at the g

125 f 27 JCV seronegative patients, 10 (37%) had JCV viruria.

126 9 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells.

127 sue samples from donors (18 of 24) with high JCV antibody levels, 13.3% of donors with low levels i(4

128 issue samples of donors (32 of 71) with high JCV, 2.2% of donors with low JCV serostatus (2 of 93), a

129 suppressed patients had significantly higher JCV DNA levels in brain, compared with immunocompetent p

130 This expands the spectrum of identified JCV diseases associated with broad-spectrum immunosuppre

131 4(+) T-cell responses against the identified JCV variant and subsequently resulted in a decline of CD

132 During immunosuppression, JCV can infect the brain, causing a demyelinating diseas

133 munosuppression and suggest new paradigms in JCV latency, compartmentalization, and reactivation.

134 the protein to inhibit its critical roles in JCV infection.

135 in-depth analysis of 14 brain-infiltrating, JCV-specific CD4(+) T cell clones demonstrated that thes

136 ide interactions used by brain-infiltrating, JCV-specific CD4(+) T cells has not, to our knowledge, b

137 veral years, indicating that once initiated, JCV infection may not entirely clear, even with IRIS.

138 remained asymptomatic following inoculation, JCV DNA was occasionally detected in both the blood and

139 ction assay confirmed the presence of intact JCV virions inside the B cells.

140 re no animal models available to investigate JCV pathogenesis.

141 e were inoculated with either a PML isolate, JCV Mad-4, or with JCV CY, found in the kidney and urine

142 ed by the human neurotropic polyomavirus JC (JCV) and is found almost exclusively in individuals with

143 of the brain caused by the polyomavirus JC (JCV), has evolved tremendously.

144 on of the glia by the JC polyomavirus (JCV); JCV granule cell neuronopathy is caused by infection wit

145 Higher kidney JCV DNA load was strongly associated with higher brain J

146 rotected against lethal challenge with LACV, JCV, and Tahyna virus (TAHV).

147 progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy.

148 f 71) with high JCV, 2.2% of donors with low JCV serostatus (2 of 93), and 0% of seronegative persons

149 Mean JCV loads were significantly higher than those of BKV in

150 Measuring JCV DNA in blood or urine with currently available metho

151 Thus, a negative JCV antibody result should not be conflated with absence

152 ent CD4(+) T-cell recognition of neurotropic JCV variants is crucial to support CD8(+) T cells in com

153 The data indicate that no JCV-related specific T- and B-cell expansions were mount

154 le cell neuronopathy associated with a novel JCV mutation.

155 Naturally occurring JCV sequence variation, together with drug treatment-ind

156 sult should not be conflated with absence of JCV infection.

157 Serostatus was associated with amounts of JCV DNA in urine and its tissue distribution.

158 Analysis of JCV from multiple biofluids revealed that individuals we

159 However, clearance of JCV was not efficient, because mutations in the major ca

160 Intracerebral delivery of JCV resulted in infection and subsequent demyelination o

161 uisite specificity for conserved epitopes of JCV large T antigen.

162 These results provide evidence of JCV latency in the brain prior to severe immunosuppressi

163 s caused by infection with a mutated form of JCV, leading to a shift in viral tropism from the glia t

164 been thought to be the nonpathogenic form of JCV.

165 ssing the attachment/fusion glycoproteins of JCV.

166 tiation to CD19+ cells that favors growth of JCV.

167 ystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the struc

168 istence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconsti

169 However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the

170 termed G144, that supports robust levels of JCV DNA replication, a central part of the JCV life cycl

171 h infection by JC virus and robust levels of JCV DNA replication.

172 dvance toward understanding the mechanism of JCV pathogenesis and the identification of drugs to trea

173 Mutations of JCV capsid viral protein 1 (VP1), the capsid protein inv

174 a clinical sample with a high copy number of JCV or a plasmid control.

175 hese cases may show long-term persistence of JCV and delayed clinical improvement despite inflammatio

176 another patient with neuronal persistence of JCV revealed strong infiltration of CD8(+) T cells and c

177 Persistence of JCV was associated with a lack of JCV VP1-specific T-cel

178 ccination of mice with 10(1) or 10(3) PFU of JCV/LACV protected against lethal challenge with LACV, J

179 hybridization data confirmed the presence of JCV DNA in the brains of patients without PML.

180 luid analysis did not reveal the presence of JCV DNA.

181 oreover, recent data suggest the presence of JCV in bone marrow plasma cells.

182 The spectrum of presentations of JCV-related disease has evolved over time and may challe

183 The detection and quantification of JCV from the tissues by quantitative polymerase chain re

184 ng key pathways needed for the regulation of JCV DNA replication, and identifying inhibitors of this

185 he evidence for infection and replication of JCV in B cells is unclear.

186 um antibody test by comparing the results of JCV serology to JCV viruria and viremia in 67 patients e

187 Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalu

188 and Epstein-Barr virus (EBV) at sequences of JCV found infecting the brain.

189 Sequencing of JCV CSF strain showed an archetype-like regulatory regio

190 To determine sites of JCV persistence in immunologically healthy individuals.

191 th John Cunningham virus (JCV), the sites of JCV persistence remain incompletely characterized.

192 for a number of purposes, such as studies of JCV infection, establishing key pathways needed for the

193 dendrocyte-based model system for studies of JCV-dependent PML.

194 tion is a model for conferring advantages on JCV in the brain.

195 In 5 patients who developed PML, JCV DNA was not detected in blood at any time point befo

196 eatment with interleukin 7, JC polyomavirus (JCV) capsid protein VP1, and a Toll-like receptor 7 agon

197 relationship between latent JC polyomavirus (JCV) infection and progressive multifocal leukoencephalo

198 l nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and m

199 nfection of the glia by the JC polyomavirus (JCV); JCV granule cell neuronopathy is caused by infecti

200 ng infections caused by human polyomaviruses JCV and BKV.

201 scriptional profile necessary for productive JCV infection.

202 Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells

203 testing the safety of natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) pati

204 inhibitor of N-linked glycosylation, reduced JCV infection.

205 e established that the Akt pathway regulates JCV DNA replication and that JCV DNA replication can be

206 Persistent (latent or actively replicating) JCV infection mostly predominates in genitourinary tissu

207 Serum JCV antibody status was determined by enzyme-linked immu

208 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in

209 PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue nata

210 ion, HCS areas were associated with striking JCV-associated demyelination of cortical and subcortical

211 now, there has been no animal model to study JCV in the brain, and research into treatment has relied

212 In this study, JCV DNA was quantified by real-time polymerase chain rea

213 This model may prove valuable for studying JCV host immune responses.

214 affect the capacity of 5-HT(2A)R to support JCV infection and did not alter the cell surface express

215 t the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay i

216 potentially oncogenic viruses such as SV40, JCV, BKV and EBV in patient-derived colorectal carcinoma

217 thway regulates JCV DNA replication and that JCV DNA replication can be inhibited by MK2206, a compou

218 idney and liver transplant patients and that JCV may have a role in renal dysfunction in some solid o

219 These data confirm that JCV in natalizumab-PML patients is similar to that obser

220 These data confirm that JCV nonproductively infects B cells and possibly uses th

221 thiocyanate-conjugated JCV demonstrated that JCV enters the B cells, and DNase protection assay confi

222 Furthermore, we have determined that JCV DNA replication in G144 cells is stimulated by myris

223 The JCV/LACV chimeric virus contains full-length S and L seg

224 Accordingly, the JCV serological antibody test is of paramount importance

225 ned by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemic

226 uencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that

227 xamine the current state of knowledge of the JCV life cycle and mechanisms of pathogenesis.

228 We will discuss the normal course of the JCV life cycle including transmission, primary infection

229 f JCV DNA replication, a central part of the JCV life cycle.

230 ients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding r

231 Furthermore, analysis of the JCV regulatory region sequences showed both rearranged a

232 The false-negative rate of the JCV serology in this study was 37%; therefore, JCV seros

233 We tested the accuracy of the JCV serum antibody test by comparing the results of JCV

234 Intriguingly, several of the JCV standards sequenced in this study with large T antig

235 V serology in this study was 37%; therefore, JCV serostatus does not appear to identify all patients

236 tein expression, and the replication of this JCV mutant was significantly reduced, suggesting that Le

237 In nongenitourinary tissues, JCV DNA was detected in 45.1% of tissue samples of donor

238 nkeys and induced neutralizing antibodies to JCV, LACV, and TAHV.

239 addition, the susceptibility of CRC cells to JCV and BKV was examined using a long-term cultivation a

240 by comparing the results of JCV serology to JCV viruria and viremia in 67 patients enrolled in a sin

241 iscordance may be important in understanding JCV biology, risk for PML, and PML pathogenesis.

242 f the virus appear to correlate with urinary JCV shedding and serostatus.

243 Urine JCV DNA copy numbers were significantly higher in the se

244 ure enzyme-linked immunosorbent assay, using JCV-VP1 fused to glutathione S-transferase as antigen.

245 sse virus (LACV) and Jamestown Canyon virus (JCV), family Bunyaviridae, are mosquito-borne viruses th

246 ee risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use

247 own about dynamics of John Cunningham virus (JCV) in nonkidney organ transplant patients.

248 as been infected with John Cunningham virus (JCV), the sites of JCV persistence remain incompletely c

249 ection, as many viruses, including JC virus (JCV) and HIV, cannot replicate in rodent cells.

250 n is a small regulatory protein of JC virus (JCV) and is required for the successful completion of th

251 in all patients, notably including JC virus (JCV) and Torque teno virus (TTV) and interestingly, we d

252 n to define the prevalence of anti-JC virus (JCV) antibodies in multiple sclerosis (MS) patients and

253 sociated with the presence of anti-JC virus (JCV) antibodies.

254 A 55-year-old, JC virus (JCV) antibody-positive patient with multiple sclerosis w

255 JC virus (JCV) causes progressive multifocal leukoencephalopathy (

256 lution and relative copy number of JC virus (JCV) clinical standards.

257 the clinical utility of measuring JC virus (JCV) DNA in blood or urine of natalizumab-treated multip

258 JC virus (JCV) DNA in the cerebrospinal fluid (CSF) provides the l

259 JC virus (JCV) infection is a lytic infection of oligodendrocytes

260 al demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes, may develop in patie

261 b-treated MS patients is linked to JC virus (JCV) infection.

262 JC virus (JCV) is a human polyomavirus and the causative agent of

263 JC virus (JCV) is latent in the kidneys and lymphoid organs of hea

264 JC virus (JCV) is the etiologic agent of progressive multifocal le

265 Infection with JC virus (JCV) may lead to development of demyelinating progressiv

266 d either using cerebrospinal fluid JC virus (JCV) polymerase chain reaction, brain biopsy, or autopsy

267 JC virus (JCV) seropositivity is a risk factor for progressive mul

268 ausing members (BK virus (BKV) and JC virus (JCV)) identified.

269 evastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persisten

270 ukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for mu

271 pecific primers to detect DNA from JC virus (JCV), varicella zoster virus (VZV), cytomegalovirus (CMV

272 st common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and

273 unosorbent assay (ELISA) to detect JC virus (JCV)-specific antibodies in multiple sclerosis (MS) pati

274 nfection with the human gliotropic JC virus (JCV).

275 ning the productive replication of JC virus (JCV).

276 caused by the reactivation of the JC virus (JCV).

277 ing disease of the brain caused by JC virus (JCV).

278 iduals are infected with the human JC virus (JCV).

279 viral pathogens including JC polyoma virus (JCV) infection.

280 mbination between polyomavirus JC (JC virus [JCV]) and Epstein-Barr virus (EBV) at sequences of JCV f

281 es simplex virus 1 [HSV-1], HSV-2, JC virus [JCV], and varicella-zoster virus [VZV]).

282 Seven of 12 individuals were JCV antibody seropositive based on absorbance units.

283 Forty (59.7%) of the 67 patients were JCV seropositive.

284 When JCV actively replicates in oligodendrocytes and astrocyt

285 Whether JCV can also cause meningitis has not yet been demonstra

286 Whether JCV is present in the brains or other organs of healthy

287 ch JCV replicates, and lymphocytes, in which JCV is likely latent.

288 onality between cells of the brain, in which JCV replicates, and lymphocytes, in which JCV is likely

289 ervous system manifestations associated with JCV infection include granule cell neuronopathy, encepha

290 Cl values were significantly associated with JCV shedding in both kidney and liver recipients (P< .00

291 Epstein-Barr virus-transformed B cells with JCV and found that the viral genome decreased >1000-fold

292 When vaccinated monkeys were challenged with JCV, they were protected against the development of vire

293 These results were correlated with JCV antibody levels.

294 and IRIS, and correlates histologically with JCV focal leukocortical encephalitis.

295 ppear to identify all patients infected with JCV.

296 he 67 patients were previously infected with JCV.

297 When challenged intracerebrally with JCV, these mice exhibit some of the characteristics of P

298 ith either a PML isolate, JCV Mad-4, or with JCV CY, found in the kidney and urine of healthy individ

299 ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03).

300 ex vivo and after in vitro stimulation with JCV peptides.