Acute Hepatitis C Virus Structural Gene Sequences as Predictors of Persistent Viremia: Hypervariable Region 1 as a Decoy

Abstract

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.

Epitope Mapping Porcine Reproductive and Respiratory Syndrome Virus by Phage Display: the nsp2 Fragment of the Replicase Polyprotein Contains a Cluster of B-Cell Epitopes

“…6) can at present only be guessed at, the interplay between hypervariable epitope sites in viral envelope glycoproteins and the host antibody response is thought to be of importance for the pathogenesis of, for example, human immunodeficiency virus and hepatitis C virus infections. For those viruses, linear strongly antigenic envelope glycoprotein sequences have in some cases been shown to be decoy epitopes, which lure the host antibody response away from critical, neutralizing epitope sites (4,33). ES12 exhibited some features expected of a decoy epitope, such as the ability to induce very high antibody levels rapidly and consistently in all infected animals ( Table 3 and Fig.…”

HCV selection and HVR1 evolution in a chimpanzee chronically infected with HCV‐1 over 12 years

“…15,21 The evolution of HVR1 allows the development of immune escape mutants and the establishment of a chronic carrier state. 6,[26][27][28] Long-term changes of HVR1 have been analyzed in epidemiologically linked individuals. The nearly identical majority of HVR1 patterns from an infection source were observed in different recipients and remained invariant until acute hepatitis developed.…”

Pretransplantation hepatitis C virus quasispecies may be predictive of outcome after liver transplantation

“…[12][13][14][15][16] This region is analogous to the V3 loop of the human immunodeficiency virus (HIV), which contains a principal neutralization domain. 17 In the nontransplantation setting, alcoholic patients infected with HCV 18 as well those infected with HCV with persistent viremia or advanced sequelae were demonstrated to exhibit a greater diversity of quasispecies in the circulating pool [19][20][21] and in liver tissue. 22 Also in a nontransplantation setting, quasispecies distribution within the liver has been observed to differ from the distribution in the circulation [23][24][25][26][27][28] or even in different parts of the liver.…”