Role of the innate immune defenses in viral infections

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Hepatitis C virus (HCV) infection is a global health problem affecting 70 million people worldwide, resulting in liver failure and hepatocellular carcinoma. Despite the development of effective antivirals, the number of new infections is increasing in many countries, and treated patients are not protected from re-infection. Therefore, the development of a vaccine is urgently required to eradicated HCV. While successful vaccines against other pathogens are typically based on potent and long-lived antibody responses, the longevity and breadth of such responses to HCV remain unknown. The availability of effective antiviral therapies allowed us to determine the half-life of naturally induced HCV-specific antibodies and the role of antigen in maintaining B cell responses. We used a panel of panels of 4 cell culture produced HCV strains and 19 HCV pseudoparticles with different HCV envelope sequences to study the neutralizing activity of sera from 24 patients. The patient sera were serially collected up to 18 years after treatment-induced HCV clearance. In addition, we assessed the phenotype of HCV-specific B cells in 48 patients by flow cytometry using a fluorochrome-conjugated HCV-envelope probe, and assessed the differentiation of B cells into antibody-secreting cells (ASC) cell culture and Elispot assay. Prior to treatment, patients displayed neutralizing antibodies with cross-reactivity against multiple HCV viruses and pseudoparticles. HCV-specific memory B cells were more activated than total memory B cells, which was HCV antigen-dependent. After treatment-induced HCV clearance, both potency and breadth of the serum neutralizing activity declined rapidly with a half-life of 4.8 - 7.3 years. Fourteen of 17 patients had no detectable neutralizing activity against HCV genotype 1a, and 12 out of 19 HCV pseudoparticles were not neutralized at 7 years post successful antiviral treatment. In contrast, HCV-specific memory B cells persisted until the end of the follow up period in all patients and maintained their ability to differentiate into antibody-secreting cells. In conclusion, HCV neutralizing activity decays rapidly after treatment-induced HCV clearance. The persistence of HCV-specific memory B cells and the absence of inflammation after viral clearance provide an opportunity to induce protective immunity by vaccination.