We hypothesized that hepatitis C virus (HCV) persistence is related to the sequence variability of putative envelope genes. This hypothesis was tested by characterizing quasispecies in specimens collected every six months from a cohort of acutely HCV-infected subjects (mean duration of specimen collection, 72 months after seroconversion). We evaluated 5 individuals who spontaneously cleared viremia and 10 individuals with persistent viremia by cloning 33 1-kb amplicons that spanned E1 and the 5′ half of E2, including hypervariable region 1 (HVR1). To assess the quasispecies complexity and to detect variants for sequencing, the first PCR-positive sample was examined by using a previously described method that combines heteroduplex analysis and analysis of single-stranded conformational polymorphisms. The ratio of nonsynonymous to synonymous substitutions (dN/dS
) within each sample was evaluated as an indicator of relative selective pressure. Amino acid sequences were analyzed for signature patterns, glycosylation signals, and charge. Quasispecies complexity was higher and E1dN/dS
ratios (selective pressure) were lower in those with persistent viremia; the association with persistence was strengthened by the presence of a combination of both characteristics. In contrast, a trend toward higher HVR1dN/dS
ratios was detected among those with persistent viremia. We did not detect any such association for factors that may affect complexity such as serum HCV RNA concentration. HVR1 had a lower positive charge in subjects with persistent viremia, although no consistent motifs were detected. Our data suggest that HCV persistence is associated with a complex quasispecies and immune response to HVR1.
Nonalcoholic fatty liver disease (NAFLD) is the preferred term to describe the spectrum of liver damage ranging from hepatic steatosis to steatohepatitis, liver fibrosis, and cirrhosis, and it is emerging as the most common liver disease in industrialized countries. Thus, the discovery of food components that would ameliorate NAFLD is of interest. Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid, has attracted considerable attention because of its potentially beneficial biological effects both in vitro and in vivo. We tested whether dietary CLA protects Zucker (fa/fa) rats from hepatic injury. After 8 wk of feeding, hepatomegaly, hepatic triglyceride (TG) accumulation, and elevated hepatic injury markers in plasma were markedly alleviated in CLA-fed Zucker rats compared with linoleic acid-fed (control) rats. These effects were attributed in part to the enhanced hepatic activities of carnitine palmitoyltransferase, a key enzyme of fatty acid beta-oxidation, and microsomal TG transfer protein, an important factor for lipoprotein secretion due to the CLA diet. We previously reported that the severe hyperinsulinemia in control Zucker rats was attenuated in CLA-fed rats due to an enhanced level of plasma adiponectin, which improves insulin sensitivity. In the present study, the adiponectin concentration was increased and the mRNA expression of tumor necrosis factor-alpha, an inflammatory cytokine, was markedly suppressed in the liver of CLA-fed Zucker rats. We speculate that the enhanced level of liver adiponectin may prevent the development and progression of NAFLD in CLA-fed Zucker rats.
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