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Published on: June 26, 2014
Analysis of hepatitis C virus hypervariable region 1 sequence from cryoglobulinemic patients and associated controls
Gabriella Bianchettin1, Claudia Bonaccini, Romina Oliva
1Area Infettivologica, Dipartimento di Malattie Infettive, IRCCS Policlinico San Matteo, Via Taramelli 5, 27100 Pavia, Italy.
Insights
Specific changes in the hepatitis C virus (HCV) hypervariable region 1 (HVR1) are unlikely to cause cryoglobulinemia. Host factors, not viral mutations, likely drive this HCV complication.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Chronic hepatitis C virus (HCV) infection is linked to extrahepatic manifestations, including B-cell lymphoproliferative disorders.
- Specific amino acid sequences in HCV's hypervariable region 1 (HVR1) have been hypothesized to correlate with cryoglobulinemia.
Purpose of the Study:
- To investigate the association between HVR1 sequence variations and cryoglobulinemia in chronic HCV patients.
- To determine if specific viral mutations are responsible for cryoglobulinemia development in HCV infection.
Main Methods:
- Sequence analysis of HVR1 in 80 symptomatic/asymptomatic chronic HCV patients with cryoglobulins and 33 without.
- Application of statistical and bioinformatics tools: Fisher's exact test, k-means clustering, Tree determinant-residue identification, mutation correlation, PCA, and phylogenetic analysis.
Main Results:
- Prevalence of HVR1 insertions was similar in patients with (6.2%) and without (9.1%) cryoglobulins, contradicting previous findings.
- Statistical and bioinformatics analyses revealed no significant differences in HVR1 sequences between cryoglobulin-negative and -positive patients.
- No direct link was found between specific HCV envelope sequence distribution and pathological B-cell proliferation.
Conclusions:
- Cryoglobulinemia in chronic HCV infection is likely driven by host-specific factors rather than specific viral sequences in HVR1.
- The study suggests that viral factors within HVR1 are not the primary cause of cryoglobulinemia in HCV patients.
Abstract:
Chronic hepatitis C virus (HCV) infection is frequently associated with extrahepatic manifestations, including nonmalignant and malignant B-cell lymphoproliferative disorders. It has been reported that specific changes or recurring motifs in the amino acid sequence of the HCV hypervariable region 1 (HVR1) may be associated with cryoglobulinemia. We searched for specific insertions/deletions and/or amino acid motifs within HVR1 in samples from 80 symptomatic and asymptomatic patients with and 33 patients without detectable cryoglobulins, all with chronic HCV infection. At variance with the results of a previous study which reported a high frequency of insertions at position 385 of HVR1 from cryoglobulinemic patients, we found a 6.2% prevalence of insertions in samples from patients with and a 9.1% prevalence in those without cryoglobulinemia. Moreover, statistical and bioinformatics approaches including Fisher's exact test, k-means clustering, Tree determinant-residue identification, correlation of mutations, principal component analysis, and phylogenetic analysis failed to show statistically significant differences between sequences from cryoglobulin-negative and -positive patients. Our findings suggest that cryoglobulinemia may arise by virtue of as-yet-unidentified host- rather than virus-specific factors. Specific changes in HCV envelope sequence distribution are unlikely to be directly involved in the establishment of pathological B-cell monoclonal proliferation.
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