Insertion and recombination events at hypervariable region 1 over 9.6 years of hepatitis C virus chronic infection

Abstract

Hepatitis C virus (HCV) exists as a quasispecies within an infected individual. We have previously reported an in-frame 3 bp insertion event at the N-terminal region of the E2 glycoprotein from a genotype 4a HCV isolate giving rise to an atypical 28 aa hypervariable region (HVR) 1. To further explore quasispecies evolution at the HVR1, serum samples collected over 9.6 years from the same chronically infected, treatment naïve individual were subjected to retrospective clonal analysis. Uniquely, we observed that isolates containing this atypical HVR1 not only persisted for 7.6 years, but dominated the quasispecies swarm. Just as striking was the collapse of this population of variants towards the end of the sampling period in synchrony with variants containing a classical HVR1 from the same lineage. The replication space was subsequently occupied by a second minor lineage, which itself was only intermittently detectable at earlier sampling points. In conjunction with the observed genetic shift, the coexistence of two distinct HVR1 populations facilitated the detection of putative intra-subtype recombinants, which included the identification of the likely ancestral parental donors. Juxtaposed to the considerable plasticity of the HVR1, we also document a degree of mutational inflexibility as each of the HVR1 subpopulations within our dataset exhibited overall genetic conservation and convergence. Finally, we raise the issue of genetic analysis in the context of mixed lineage infections.

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

“…Whereas other models of host-viral interaction predict a constant increase in genetic heterogeneity of the intrahost viral population as a result of continuous immune escape (22)(23)(24)(25), the AC model predicts a different outcome of the intrahost HCV evolution: reduction in heterogeneity of the persistent viral population. This prediction is strongly supported by experimental observations of increasing negative selection during intrahost HCV evolution, long-term persistence of viral variants, and substantial heterogeneity loss associated with a strong negative selection after years of infection (9)(10)(11)(12)(13)(14).…”

“…The late-stage HCV populations were shown to remain constant and homogeneous under the strong negative selection for years, indicating a high level of intrahost adaptation (9). Certain intrahost HCV variants were observed to persist in infected hosts for up to 16 y (9,14,15). These observations suggest that intrahost HCV subpopulations can remain unaffected by the immune system for years over the course of infection.…”

“…Thus, in-hub variants can be viewed as playing an altruistic role in AC because they improve fitness of adjacent variants at their own fitness cost, whereas adjacent variants are selfish because they gain fitness at the expense of in-hub variants. These selfish variants remain in existence without eliciting strong specific immune responses and are predicted to persist under negative selection as was recently observed (9,(11)(12)(13)(14)(15). In contrast, altruistic variants are efficiently eliminated from the viral population while their immune responses are being continuously sustained.…”

A single amino acid change in the hypervariable region 1 of hepatitis C virus genotype 4a aids humoral immune escape

“…The antibody specificity of the latter time point, i.e. T13, targeted a different HVR1 lineage from that found previously (Palmer et al, 2012(Palmer et al, , 2014. The HVR1 variant captured by the T13Ab was first observed in pyrosequencing data at T10 (1.1 %) (Palmer et al, 2014).…”

“…L1 dominated the virome for the first 8 years of the sampling period prior to population collapse and this led to the concomitant rise to prominence of L2. During the initial dominance of L1, IgG targeting of L1 was detected in five of the first seven samples which, in part, contributed directly to the extinction of this group of variants (Palmer et al, 2012(Palmer et al, , 2014. In spite of the near total dominance of L2 sequences in later samples (96.9 and 99.9 % at T9 and T10, respectively; see Fig.…”