Acceleration of Hepatitis C Virus Envelope Evolution in Humans Is Consistent with Progressive Humoral Immune Selection during the Transition from Acute to Chronic Infection

Abstract

During the transition from acute to chronic infection in individuals persistently infected with hepatitis C virus (HCV), cellular responses initiate within the first 6 months of primary infection and collapse thereafter, whereas humoral responses activate later during the chronic phase. Whether and how this deviation of immune responses specifically influences HCV evolution are unknown. To determine the pattern of HCV evolution during this critical period, we conducted extensive sequence analysis on annual clonal hemigenomic sequences for up to 3 years in six well-characterized subjects, using statistical methods that accounted for repeated measures. Significantly different evolutionary rates were observed in envelope versus nonenvelope genes, with an increasing rate of nonsynonymous change (dN) in envelope genes and a stable dN in nonenvelope genes (P ‫؍‬ 0.006). The ratio of the envelope to nonenvelope nonsynonymous rate increased from 2 in year 1 to 5 in years 2 and 3. Centripetal changes (reversions toward matching of the worldwide subtype 1a consensus sequence) were frequently observed during the 3-year transition from acute infection to chronicity, even in the presence of neutralizing antibody (NAb) pressure. Remarkably, sequences of hypervariable region 1 (HVR1) remained stable for up to 21 months in the absence of NAb pressure in one subject, followed by rapid changes that were temporally associated with the detection of NAb responses, which strongly suggests that HVR1 evolution is shaped by NAb pressure. These data provide the first systematic estimates of HCV evolutionary rates in multiple genes during early infection in vivo and provide additional evidence for deterministic, rather than random, evolution of HCV.Worldwide, an estimated 170 million people are infected with hepatitis C virus (HCV) (2, 58). Following acute infection, which is usually asymptomatic, 60 to 80% of infected individuals develop persistent infection, which is still the leading cause of hepatocellular carcinoma and liver transplantation in the United States (33,39,53). Only pegylated alpha interferon and ribavirin are approved for treating this virus, and no successful vaccine has been developed (48).The extraordinary evolution and diversity of HCVs are major challenges for vaccine design and drug development. HCV replicates to high levels using an error-prone polymerase (36), thereby generating in each host a spectrum of closely related but distinct viral variants called quasispecies (6, 34). Quasispecies distributions containing variants with a range of characteristics facilitate viral escape from selective pressure, balanced by fitness constraints that drive reversion to restore fitness, as has been demonstrated in controlled experiments involving simian immunodeficiency virus (SIV) under immune selective pressure and HCV under selective pressure from small-molecule inhibitors (17,46). Similarly, HCV has been observed to escape selective pressure of the host immune response, demonstrating evidence of both escape and reversion ...

Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis

“…We previously demonstrated that the evolutionary dynamics of HCV during early infection predicts the outcome of acute hepatitis C, such that a decrease in viral diversity correlates with viral clearance whereas an increase correlates with progression to chronicity (11). These data, subsequently corroborated elsewhere (12)(13)(14), are consistent with the concept that aspects of viral evolution reflect the strength of virus-specific adaptive immune responses and therefore the ability of the host to control the virus (8,15). However, little is known about the correlations among adaptive immunity, HCV evolution, and rates of disease progression once chronic hepatitis C is established.…”

Emerging concepts in immunity to hepatitis C virus infection

“…The use of retroviral pseudoparticles bearing autologous HCV glycoproteins (HCVpp) from the initial inoculum allowed the precise examination of strain-specific neutralization. The late phase of chronic infection is accompanied by the induction of NAb responses as well as an increasing rate of envelope viral sequence evolution (106), indicative of ongoing humoral selection pressure. Viral escape may occur through several additional mechanisms (108), including an impaired cross-neutralizing activity that selects the outgrowth of viral variants and the interplay of HCV glycoproteins with HDL and the scavenger receptor SR-BI ( Figure 1A), which can prevent the effect of NAbs and enhance cell entry of HCV and infection (109).…”

“…Whether the humoral response plays an important role in controlling HCV infection remains controversial (105,106); indeed, the fact that hypogammaglobulinemic humans can spontaneously eradicate HCV (107) may suggest that antibody responses are dispensable. Studies showing a lack of association between neutralizing antibodies (NAbs) and viral clearance were confounded by poorly defined viral inoculum and heterogeneous patient populations.…”

Experimental models to study the immunobiology of hepatitis C virus

“…This notion is further supported by the finding that the sequence of HVR1 is less variable in the absence of neutralizing antibodies. This rapidly changes, however, when neutralizing antibodies emerge, indicating evolution of viral variants in response to pressure from neutralizing antibodies (Dowd et al, 2009; Farci et al, 2000;Liu et al, 2010). Importantly, it has been shown that amino acid substitutions in HVR1 are responsible for a dramatic decrease in neutralization sensitivity over time (Dowd et al, 2009).…”