Long-Term Evolution of the Hypervariable Region of Hepatitis C Virus in a Common-Source-Infected Cohort

Abstract

The long-term evolution of the hepatitis C virus hypervariable region (HVR) and flanking regions of the E1 and E2 envelope proteins have been studied in a cohort of women infected from a common source of anti-D immunoglobulin. Whereas virus sequences in the infectious source were relatively homogeneous, distinct HVR variants were observed in each anti-D recipient, indicating that this region can evolve in multiple directions from the same point. Where HVR variants with dissimilar sequences were present in a single individual, the frequency of synonymous substitution in the flanking regions suggested that the lineages diverged more than a decade previously. Even where a single major HVR variant was present in an infected individual, this lineage was usually several years old. Multiple lineages can therefore coexist during long periods of chronic infection without replacement. The characteristics of amino acid substitution in the HVR were not consistent with the random accumulation of mutations and imply that amino acid replacement in the HVR was strongly constrained. Another variable region of E2 centered on codon 60 shows similar constraints, while HVR2 was relatively unconstrained. Several of these features are difficult to explain if a neutralizing immune response against the HVR is the only selective force operating on E2. The impact of PCR artifacts such as nucleotide misincorporation and the shuffling of dissimilar templates is discussed.

Observation of positive selection within hypervariable regions of a newly identified DNA virus (SEN virus)1

“…It is probable that the high non-synonymous mutation rate re£ects immune pressure exerted as the HVR resulting in the positive selection of persistent variants. Similar immune selection has been found to take place in the V3 loop of gp120 in HIV-1 [20], the tax gene of human T-cell leukemia virus-1 [21], and the HVR in the E2 region of HCV [22,23].…”

Viral Quasispecies Evolution

“…The vast heterogeneity of the HCV that replicates in an infected patient has been amply documented by molecular cloning and Sanger sequencing and recently by application of ultradeep sequencing (543,584). HCV evolves at rates that are in the range of 10 Ϫ2 to 10 Ϫ3 substitution per site per year (499).…”

Evolutionary analysis of the dynamics of viral infectious disease

“…Known chains of transmission have been used to measure the rate of HIV evolution 57 (BOX 2) and the magnitude of the bottleneck in virus diversity generated at transmission 58 . The Irish anti-D cohort -a well-studied group of HCV-infected women who were accidentally infected with almost identical strains at the same time -has also provided valuable information about variation in viral evolution, host immune selection and disease outcome between patients 59,60 . Using a different HCV transmission cluster, Wrobel et al 61 demonstrated that molecular clock methods can reliably estimate the date that a patient was infected.…”