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Journal of Virology, May 2007, p. 4564-4571, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02104-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Analysis of Hepatitis C Virus Hypervariable Region 1 Sequence from Cryoglobulinemic Patients and Associated Controls

Gabriella Bianchettin,¹ Claudia Bonaccini,^2, Romina Oliva,^2,# Anna Tramontano,^2,3 Agostino Cividini,^1,4 Milvia Casato,⁵ Giampaolo Merlini,⁶ Enrico Silini,⁷ and Mario U. Mondelli^1,4*

Area Infettivologica e Centro di Epatologia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy,¹ Dipartimento di Biochimica, Università La Sapienza, Roma, Italy,² Istituto Pasteur-Fondazione Cenci Bolognetti, Università La Sapienza, Roma, Italy,³ Dipartimento di Malattie Infettive, Università di Pavia, Pavia, Italy,⁴ Dipartimento di Medicina Clinica, Università La Sapienza, Roma, Italy,⁵ Area di Biotecnologie e Tecnologie Biomediche, Fondazione IRCCS Policlinico S. Matteo and Università di Pavia, Italy,⁶ Dipartimento di Patologia e Medicina di Laboratorio, Università di Parma, Parma, Italy⁷

Received 26 September 2006/ Accepted 13 February 2007

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.

Published ahead of print on 21 February 2007.

Present address: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Firenze, Italy.

^# Present address: Dipartimento di Scienze Applicate, Università degli Studi di Napoli "Parthenope," Napoli, Italy.

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