Different Hepatitis C Virus (HCV) RNA Load Profiles Following Seroconversion among Injecting Drug Users without Correlation with HCV Genotype and Serum Alanine Aminotransferase Levels

Beld, Marcel; Penning, Maarten; McMorrow, Martin; Gorgels, J. P. M. C.; Hoek, Anneke van den; Goudsmit, Jaap

doi:10.1128/jcm.36.4.872-877.1998

Cited by 44 publications

(20 citation statements)

References 30 publications

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“…It is well established that persistent viruses such as HCV and human immunodeficiency virus can lead to T-cell exhaustion and senescence by encoding or altering the expression and function of miRNAs that target cellular and viral mRNAs to regulate viral replication and cell functions. [15][16][17][18][19][20] In order to identify human miRNAs involved in regulating T-cell responses during HCV infection, we compared miRNA arrays in CD4 1 T cells from chronically HCV-infected individuals versus HS. A total of 384 well-known miRNAs were measured in this array.…”

Section: Resultsmentioning

confidence: 99%

Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

Zhou

Ying

et al. 2015

Hepatology

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T cells play a crucial role for viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. microRNAs (miR) have been implicated as key regulators controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4+ T cell responses via over-expression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with over-expression of DUSP6 were observed in CD4+ T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 over-expression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4+ T cells led to improved T cell responses including enhanced CD25 and CD69 expressions, increased IL-2 expression, and improved proliferation of CD4+ T cells derived from chronically HCV-infected individuals. Since a decline of miR-181a concomitant with DUSP6 over-expression are the signature markers for age-associated T cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T cell aging via miR-181a-regulated DUSP6 signaling, and reveal new targets for therapeutic rejuvenation of impaired T cell responses during chronic viral infection.

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Section: Resultsmentioning

confidence: 99%

Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

Zhou

Ying

et al. 2015

Hepatology

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“…In March 1996, we selected individuals who had been followed for at least 3 years and seen at least seven times (n ϭ 358), and 19 HCV seroconverters were identified as described elsewhere. 25 Of these 19 HCV seroconverters, 10 remained HIV-seronegative during the study period, whereas 3 seroconverted for HIV just before the end of follow-up. The average sampling interval among the 13 individuals during their HIVnegative status was 4 months (range, 1-12 months), with an average of 16 time points per patient (range, 6-26 time points), and with an average follow-up of 61 months (range, 16-114 months).…”

Section: Methodsmentioning

confidence: 99%

“…HCV RNA was isolated and detected using primers located in the highly conserved 5Ј-UTR region in a single reversetranscription polymerase chain reaction (RT-PCR) under conditions as described elsewhere. 25 For the PCR, the GeneAmp PCR carryover prevention kit (Perkin Elmer Cetus, Branchburg, NJ) was used to avoid contamination. A pool of HCV-positive serum was quantified by the branched DNA (bDNA) technology (Chiron Corporation) to a level of 1.6 ϫ 10 6 HCV RNA copies/mL, and hundredfold dilutions of the quantified serum pool were used as positive controls.…”

Section: Detection Of Hcv Rna By Reverse-transcription Polymerase Chainmentioning

confidence: 99%

Quantitative antibody responses to structural (core) and nonstructural (NS3, NS4, and NS5) hepatitis C virus proteins among seroconverting injecting drug users: Impact of epitope variation and relationship to detection of HCV RNA in blood

et al. 1999

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To gain insight into the natural history of hepatitis C virus (HCV), 13 human immunodeficiency virus (HIV)-seronegative injecting drug users were studied who seroconverted for HCV as determined by third-generation enzymelinked immunosorbent assay, showed an ensuing antibody response to HCV, and were not treated with any antiviral drugs during follow-up. Subjects included 13 untreated HIV-negative individuals, of whom 5 (38.5%) apparently cleared HCV and were polymerase chain reaction (PCR)-negative in at least 3 consecutive samples, 3 (23.1%) showed transient viremia and were PCR-negative in 1 sample during the study period, and the other 5 (38.5%) showed persistent viremia. Viremia was determined longitudinally by reverse-transcription PCR (RT-PCR) and quantified by branched DNA (bDNA). HCV genotypes were determined on serial samples during follow-up. Quantitative antibody levels to core, NS3, NS4, and NS5 were determined using the Chiron RIBA HCV-titering Strip Immunoblot Assay, which is based on HCV genotype 1. The antibody responses to core, NS3, NS4, and NS5 were erratic. In individuals infected with HCV genotype 1, significantly higher median antibody responses to core (P ‫؍‬ .02) and to NS4 (P ‫؍‬ .04) were found as compared with those infected with other genotypes, showing a significant impact of HCV genotype specificity of the assay. In groups infected with HCV genotype 1, significantly higher median

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“…Four were HIVpositive before HCV-seroconversion and two experienced an acute HIV-infection at the time of HCV-infection. Seven of 19 (39%) HCV-seroconverters resolved HCV-infection [19]. All HCV-seroconverters were studied longitudinally for the presence of HCV RNA [20].…”

Section: Study Subjectsmentioning

confidence: 99%

“…Comparison between groups was performed using the highest observed T-cell response. The median time to development of the highest observed T-cell response was 11 months (range 4-23) in resolvers and 19 months (range [15][16][17][18][19][20][21][22][23][24] in chronic carriers ( Fig. 1).…”

Section: T-cell Analysesmentioning

confidence: 99%

HCV‐specific T‐cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance

Ruys

Nanlohy

Berg

et al. 2008

Journal of Viral Hepatitis

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SUMMARY. In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-c Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-Tcell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.

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Different Hepatitis C Virus (HCV) RNA Load Profiles Following Seroconversion among Injecting Drug Users without Correlation with HCV Genotype and Serum Alanine Aminotransferase Levels

Cited by 44 publications

References 30 publications

Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

Quantitative antibody responses to structural (core) and nonstructural (NS3, NS4, and NS5) hepatitis C virus proteins among seroconverting injecting drug users: Impact of epitope variation and relationship to detection of HCV RNA in blood

HCV‐specific T‐cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance

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