Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes.
Differences in the composition of the hepatitis C virus (HCV) quasispecies between plasma and blood mononuclear cells (BMC) strongly suggest that BMCs support viral replication. We examined the frequency of such compartmentalization, the cell types involved, the constraints exerted on the different variants, and the role of immunoglobulin-complexed variants. We screened the hypervariable region (HVR1) of HCV isolates from 14 HBsAg- and HIV-seronegative patients with chronic HCV infection. HCV RNA was amplified and cloned from plasma, the immunoglobulin G (IgG)-bound fraction, and total and sorted BMCs (CD19+, CD8+, CD4+, and CD14+ cells). Compartmentalization was estimated using a matrix correlation test. The ratio of nonsynonymous/synonymous substitutions (d(N)/d(S) ratio) was calculated for each compartment. HCV RNA was detected in 3/3 BMC, 11/11 CD19+, 10/11 CD14+, 4/11 CD8+ and 0/11 CD4+ cell samples. HVR1 sequences were significantly different between plasma and at least one cellular compartment in all nine cases analyzed, and between B cells (CD19+) and monocytes (CD14+) in all five available cases. IgG-bound variants were distinct from cellular variants. D(N)/d(S) ratios were similar (n = 3) or lower (n = 6) in cellular compartments compared with plasma and the IgG-bound fraction. In conclusion, HCV compartmentalization is a common phenomenon. B cells and monocytes harbor HCV variants showing a low rate of nonsynonymous mutations, a feature that might contribute to the persistence of HCV infection.
Equipe Propre de l'Institut National de la Santé et de la Recherche Médicale (INSERM 99-41), Unité 481, Faculté de médecine X Bichat, 16 rue Huchard, Paris, France.
Delphine
D
Ducoulombier
Anne-Marie
AM
Roque-Afonso
Gaëtana
G
Di Liberto
François
F
Penin
Rachid
R
Kara
Yolande
Y
Richard
Elisabeth
E
Dussaix
Cyrille
C
Féray
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000821:virology*; D019277:Entropy; D005260:Female; D014644:Genetic Variation; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000821:virology*; D010802:Phylogeny; D010949:Plasma; D012367:RNA, Viral / Q000097:blood; D014764:Viral Proteins / Q000235:genetics
C400562:HVR1 protein, Hepatitis C virus; D007074:Immunoglobulin G; D012367:RNA, Viral; D014764:Viral Proteins