Abstract
Hepatitis C virus (HCV) is one of very few viruses that are either naturally cleared, or alternatively persist to cause chronic disease. Viral diversity and escape, as well as host adaptive immune factors, are believed to control the outcome. To date, there is limited understanding of the critical, early host-pathogen interactions. The asymptomatic nature of early HCV infection generally prevents identification of the transmitted/founder (T/F) virus, and thus the study of host responses directed against the autologous T/F strain. In this study, 14 rare subjects identified from very early in infection (4–45 days) with varied disease outcomes (n = 7 clearers) were examined in regard to the timing, breadth, and magnitude of the neutralizing antibody (nAb) response, as well as evolution of the T/F strain. Clearance was associated with earlier onset and more potent nAb responses appearing at a mean of 71 days post-infection (DPI), but these responses were narrowly directed against the autologous T/F virus or closely related variants. In contrast, a delayed onset of nAbs (mean 425 DPI) was observed in chronic progressors that appear to have targeted longitudinal variants rather than the T/F strain. The nAb responses in the chronic progressors mapped to known CD81 binding epitopes, and were associated with rapid emergence of new viral variants with reduced CD81 binding. We propose that the prolonged period of viremia in the absence of nAbs in these subjects was associated with an increase in viral diversity, affording the virus greater options to escape nAb pressure once it emerged. These findings indicate that timing of the nAb response is essential for clearance. Further investigation of the specificities of the early nAbs and the factors regulating early induction of protective nAbs is needed.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic liver disease globally[1,2]
Subject 023_Ch, as previously published, had two T/F viruses identified[13], and subject 256_Ch, had an unresolved number of variants, estimated to be between 1 and 10 (Supplementary Fig. 1). Both T/F E1E2 viruses were cloned for subject 023_Ch, and subject 256_Ch had three E1E2 variants selected for cloning, with the most frequent haplotype selected from each of the three main phylogenetic clusters
Once neutralizing antibody (nAb) did emerge in this group, the responses targeted epitopes known to be involved in cluster of differentiation 81 (CD81) binding, and rapidly drove a decrease in binding efficiency, likely as a result of the emergence of immune escape mutations
Summary
Hepatitis C virus (HCV) is a major cause of chronic liver disease globally[1,2]. Following acute infection, approximately 75% of people fail to clear the virus, resulting in chronic hepatitis[3] with progressive hepatic fibrosis and cirrhosis, liver failure and an increased risk of hepatocellular carcinoma[4,5]. One small study with two subjects has been reported and both developed broadly neutralizing nAbs (BnAbs)[20] Both subjects were likely to be non-representative as one took almost a year to clear infection (six months is taken as the typical cut off for primary infection), and the other was co-infected with two HCV strains, and both longer duration and co-infection have been shown to be associated with an increased breadth of the nAb response[21]. There is accumulating evidence from in vitro studies that modulation of host receptor usage (e.g. reduced CD81 or SRBI binding) is an important mechanism of immune escape, as the nAbs have no effective role in blocking ongoing replication[32] This has been supported by in vivo data from two small studies, each with two HCV infected patients analyzed longitudinally, which indicated that reduced CD81 receptor binding coincided with emergence of nAbs[20,33]. All three clearance outcomes documented in these studies were unusually delayed beyond 6 months post-infection
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