TT virus infection in cases of fulminant hepatic failure—evaluation by clonality based on amino acid sequence of hypervariable regions

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The significance of TT virus (TTV) infection in the pathogenesis of acute liver disease is uncertain. Serum TTV-DNA was determined by polymarase-chain reaction (PCR) methods using both hemi-nested (NG059/NG063 and NG061/NG063) and single-step (T801/T935) primers in four patients with fulminant hepatic failure and one patient with late onset hepatic failure in whom hepatitis A virus (HAV) and hepatitis B virus (HBV) markers were negative. Of these five patients, the TTV-DNA was positive in two patients with fulminant hepatic failure by both PCRs before receiving blood transfusion and/or blood-products infusion. Therapies including plasma exchange with blood hemodiafiltration was performed in both patients, and one survived. The non-survivor was an 18-year-old woman with TTV genotype 2 infection. In this patient, the TTV-DNA by PCRs with both primers was positive transiently when serum ALT levels were elevated. The survivor was a 78-year-old woman with infections of TTV genotype 1b and hepatitis C virus (HCV), in whom serum ALT levels returned to normal at 3 weeks after the start of the therapies, but fluctuated after 10 weeks. TTV-DNA measured by hemi-nested primers and HCV-RNA were negative when serum ALT levels decreased, but became positive later. Semi-quantitative PCR using single-step primers revealed that serum TTV-DNA levels changed in correlation with both serum ALT and HCV-RNA levels. Amino acid sequences of hypervariable regions were identical in six out of nine clones isolated from the sera before the therapies and sequence divergence was minimal even in the other three clones, suggesting that TTV proliferated with clonality in the process of fulminant hepatic failure. We conclude that clonally proliferating TTV may contribute to fulminant hepatic failure as a solitary infectious agent or a co-infectious agent with HCV.