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Persistence of Hepatitis C Virus Traces after Spontaneous Resolution of Hepatitis C.

Chen AY, Hoare M, Shankar AN, Allison M, Alexander GJ, Michalak TI - PLoS ONE (2015)

Bottom Line: Telaprevir entirely eliminated HCV replication in the PBMC examined.An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus.The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.

View Article: PubMed Central - PubMed

Affiliation: Molecular Virology and Hepatology Research Group, Faculty of Medicine, Memorial University, St. John's, Newfoundland and Labrador, Canada.

ABSTRACT
Hepatitis C virus (HCV) frequently causes chronic hepatitis, while spontaneous recovery from infection is infrequent. Persistence of HCV after self-limited (spontaneous) resolution of hepatitis C was rarely investigated. The current study aimed to assess incidence and robustness of HCV persistence after self-resolved hepatitis C in individuals with normal liver enzymes and undetectable virus by conventional tests. Applying high sensitivity HCV RNA detection approaches, we analyzed plasma and peripheral blood mononuclear cells (PBMC) from individuals with previous hepatitis C infection. Parallel plasma and PBMC from 24 such non-viraemic individuals followed for 0.3-14.4 (mean 6.4) years were examined. Additional samples from 9 of them were obtained 4.5-7.2 (mean 5.9) years later. RNA was extracted from 250 μl plasma and, if HCV negative, from ~5 ml after ultracentrifugation, and from ex vivo stimulated PBMC. PBMC with evidence of HCV replication from 4 individuals were treated with HCV protease inhibitor, telaprevir. HCV RNA was detected in 14/24 (58.3%) plasma and 11/23 (47.8%) PBMC obtained during the first collection. HCV RNA replicative strand was evident in 7/11 (63.6%) PBMC. Overall, 17/24 (70.8%) individuals carried HCV RNA at mean follow-up of 5.9 years. Samples collected 4.5-7.2 years later revealed HCV in 4/9 (44.4%) plasma and 5/9 (55.5%) PBMC, while 4 (80%) of these 5 PBMC demonstrated virus replicative strand. Overall, 6/9 (66.7%) individuals remained viraemic for up to 20.7 (mean 12.7) years. Telaprevir entirely eliminated HCV replication in the PBMC examined. In conclusion, our results indicate that HCV can persist long after spontaneous resolution of hepatitis C at levels undetectable by current testing. An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus. The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.

No MeSH data available.


Related in: MedlinePlus

Single-nucleotide polymorphisms in the HCV E1/E2 330-bp fragment derived from PBMC of two individuals with long-term follow-up after spontaneously resolved hepatitis C.(A) Sequence identified in PBMC after 7.4 years of observation of 15-46/F carrying HCV genotype 3a. (B) Sequence from PBMC of 20-49/F followed for 20.6 years carrying HCV genotype 1b. Seven or eight randomly selected clones were sequenced bi-directionally and their sequences compared to respective subgenotype D17763 and D11168 sequences from GenBank. The boundaries of the hypervariable region 1 (HVR1) are marked by a line. Numbers and the beginning and at the end of each reference sequence, marked as Ref, indicate nucleotide positions. Nucleotides identical to those in the reference sequence are shown as dots, different as letters, and deleted as colons.
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pone.0140312.g004: Single-nucleotide polymorphisms in the HCV E1/E2 330-bp fragment derived from PBMC of two individuals with long-term follow-up after spontaneously resolved hepatitis C.(A) Sequence identified in PBMC after 7.4 years of observation of 15-46/F carrying HCV genotype 3a. (B) Sequence from PBMC of 20-49/F followed for 20.6 years carrying HCV genotype 1b. Seven or eight randomly selected clones were sequenced bi-directionally and their sequences compared to respective subgenotype D17763 and D11168 sequences from GenBank. The boundaries of the hypervariable region 1 (HVR1) are marked by a line. Numbers and the beginning and at the end of each reference sequence, marked as Ref, indicate nucleotide positions. Nucleotides identical to those in the reference sequence are shown as dots, different as letters, and deleted as colons.

Mentions: Attempts to identify variants in the E1/E2 sequence encoding HVR1 were only partially successful because of limited material. Nonetheless, PBMC acquired after 16.1 and 20.6 years of follow-up of 15-46/F and 20-49/F, respectively, showed multiple point mutations common to all clones sequenced when compared to respective 3a or 1b references (Fig 4). The majority of these mutations occurred, as expected, in HVR1 and we believe not reported before. There were also very few (2–4) unique point mutations identified in one to 3 of 8 (15-46/F) or 7 (20-49/F) clones sequenced (Fig 4). This was consistent with a high degree of sequence homogeneity within and beyond HVR1 in PBMC analyzed.


Persistence of Hepatitis C Virus Traces after Spontaneous Resolution of Hepatitis C.

Chen AY, Hoare M, Shankar AN, Allison M, Alexander GJ, Michalak TI - PLoS ONE (2015)

Single-nucleotide polymorphisms in the HCV E1/E2 330-bp fragment derived from PBMC of two individuals with long-term follow-up after spontaneously resolved hepatitis C.(A) Sequence identified in PBMC after 7.4 years of observation of 15-46/F carrying HCV genotype 3a. (B) Sequence from PBMC of 20-49/F followed for 20.6 years carrying HCV genotype 1b. Seven or eight randomly selected clones were sequenced bi-directionally and their sequences compared to respective subgenotype D17763 and D11168 sequences from GenBank. The boundaries of the hypervariable region 1 (HVR1) are marked by a line. Numbers and the beginning and at the end of each reference sequence, marked as Ref, indicate nucleotide positions. Nucleotides identical to those in the reference sequence are shown as dots, different as letters, and deleted as colons.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608821&req=5

pone.0140312.g004: Single-nucleotide polymorphisms in the HCV E1/E2 330-bp fragment derived from PBMC of two individuals with long-term follow-up after spontaneously resolved hepatitis C.(A) Sequence identified in PBMC after 7.4 years of observation of 15-46/F carrying HCV genotype 3a. (B) Sequence from PBMC of 20-49/F followed for 20.6 years carrying HCV genotype 1b. Seven or eight randomly selected clones were sequenced bi-directionally and their sequences compared to respective subgenotype D17763 and D11168 sequences from GenBank. The boundaries of the hypervariable region 1 (HVR1) are marked by a line. Numbers and the beginning and at the end of each reference sequence, marked as Ref, indicate nucleotide positions. Nucleotides identical to those in the reference sequence are shown as dots, different as letters, and deleted as colons.
Mentions: Attempts to identify variants in the E1/E2 sequence encoding HVR1 were only partially successful because of limited material. Nonetheless, PBMC acquired after 16.1 and 20.6 years of follow-up of 15-46/F and 20-49/F, respectively, showed multiple point mutations common to all clones sequenced when compared to respective 3a or 1b references (Fig 4). The majority of these mutations occurred, as expected, in HVR1 and we believe not reported before. There were also very few (2–4) unique point mutations identified in one to 3 of 8 (15-46/F) or 7 (20-49/F) clones sequenced (Fig 4). This was consistent with a high degree of sequence homogeneity within and beyond HVR1 in PBMC analyzed.

Bottom Line: Telaprevir entirely eliminated HCV replication in the PBMC examined.An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus.The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.

View Article: PubMed Central - PubMed

Affiliation: Molecular Virology and Hepatology Research Group, Faculty of Medicine, Memorial University, St. John's, Newfoundland and Labrador, Canada.

ABSTRACT
Hepatitis C virus (HCV) frequently causes chronic hepatitis, while spontaneous recovery from infection is infrequent. Persistence of HCV after self-limited (spontaneous) resolution of hepatitis C was rarely investigated. The current study aimed to assess incidence and robustness of HCV persistence after self-resolved hepatitis C in individuals with normal liver enzymes and undetectable virus by conventional tests. Applying high sensitivity HCV RNA detection approaches, we analyzed plasma and peripheral blood mononuclear cells (PBMC) from individuals with previous hepatitis C infection. Parallel plasma and PBMC from 24 such non-viraemic individuals followed for 0.3-14.4 (mean 6.4) years were examined. Additional samples from 9 of them were obtained 4.5-7.2 (mean 5.9) years later. RNA was extracted from 250 μl plasma and, if HCV negative, from ~5 ml after ultracentrifugation, and from ex vivo stimulated PBMC. PBMC with evidence of HCV replication from 4 individuals were treated with HCV protease inhibitor, telaprevir. HCV RNA was detected in 14/24 (58.3%) plasma and 11/23 (47.8%) PBMC obtained during the first collection. HCV RNA replicative strand was evident in 7/11 (63.6%) PBMC. Overall, 17/24 (70.8%) individuals carried HCV RNA at mean follow-up of 5.9 years. Samples collected 4.5-7.2 years later revealed HCV in 4/9 (44.4%) plasma and 5/9 (55.5%) PBMC, while 4 (80%) of these 5 PBMC demonstrated virus replicative strand. Overall, 6/9 (66.7%) individuals remained viraemic for up to 20.7 (mean 12.7) years. Telaprevir entirely eliminated HCV replication in the PBMC examined. In conclusion, our results indicate that HCV can persist long after spontaneous resolution of hepatitis C at levels undetectable by current testing. An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus. The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.

No MeSH data available.


Related in: MedlinePlus