Role of the innate immune defenses in viral infections

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

In the current year, we described a case of spontaneous control of HCV viremia in a patient following virological relapse with emergence of a NS5A drug-resistant virus after therapy with sofosbuvir and velpatasvir. The case is remarkable because spontaneous control of HCV viremia was temporally related with an increase in the neutralizing activity of the patients serum. In contrast to humoral responses, there was no change in T-cell responses over time as assessed in IFN-g Elispot assays with pools of HCV peptides spanning the HCV polyprotein and a CMV peptide pool. The HCV NS5A drug-resistant mutations, A30K and V31M, also did not generate new T-cell epitopes as assessed by stimulation of PBMC with HCV peptides MPKMPGVPFI and KIMPKMPGV followed by intracellular IFN-g, IL-2 and TNF-a staining and flow cytometry. Although viremia became detectable again, likely due to viral escape from the HCV-specific antibody response, the level was lower compared to pre-treatment. Concurrent with return of viremia was the appearance of antinuclear antibodies, suggestive of polyclonal B cell activation. We had previously identified a case of spontaneous HCV clearance a year after acute infection, that was also associated with an increase in serum neutralizing activity (J Infect Dis, 20212, PMID: 22293431). Collectively, these data suggest that HCV-neutralizing humoral responses can emerge even in chronic infection. To evaluate the longevity and breadth of antibody response to HCV we used a unique cohort of patients whose blood samples were serially collected up to 18 years after treatment-induced HCV clearance. We studied serum neutralizing activity prior to and after HCV clearance against a panel of HCVcc and 19 HCVpp with different HCV envelope sequences. We found that the neutralizing activity against HCV declined rapidly with a half-life of 4.8-7.3 years, and there was no neutralization against more than half of the HCVpp at 6-10 years post-treatment start. Despite of this, HCV-specific memory B cells remained detectable in the blood and maintained their ability to differentiate into antibody-secreting cells. The persistence of HCV-specific memory B cells and the absence of inflammation after viral clearance provides an opportunity to induce protective immunity by vaccination.