Subinfectious HCV exposure

Clearance of acute HCV infection with systemic viraemia can result in T-cell-based immune protection upon reinfection. HCV-specific T-cell responses have also been detected in some individuals without any history of acute HCV infection despite frequent exposure; it has been suggested that these low-level exposures confer T-cell-mediated resistance to infection. Barbara Rehermann and colleagues thus set out to study this hypothesis.

The researchers used chimpanzees in their investigation as this in vivo model most closely represents HCV infection in humans. “We repeatedly exposed chimpanzees to human plasma with trace amounts of HCV,” explains Rehermann. “The chimpanzees developed HCV-specific T-cell responses but no quantifiable viraemia or seroconversion.” These chimpanzees were then exposed to a standard HCV challenge to examine whether these T-cell responses conferred immune protection. Interestingly, the opposite was found. The chimpanzees did not mount a memory response and de novo T-cell responses were suppressed both in the blood and in the liver. Moreover, an expansion in the number of regulatory T cells (T_REG cells) was observed. By contrast, chimpanzees that had previously cleared an acute HCV infection were able to rapidly clear a second HCV challenge.

“We refute the notion that individuals who are frequently exposed to low-dose HCV and remain negative for HCV and for antibody to HCV may have T-cell mediated protective immunity upon HCV infection,” says Rehermann. Instead the researchers suggest that clearance of a previous acute infection (with systemic viraemia) might be required to confer this protective immunity.

The number of chimpanzees included in the study was small, which precluded a statistical comparison of outcomes of HCV challenge between HCV pre-exposed and naive animals. The researchers now plan to study T_REG-cell responses in humans who are frequently exposed to HCV. “Our findings might be relevant for vaccine research and for epidemiological studies because an increased T_REG cell number in frequently exposed individuals and in endemic areas might reduce the response to vaccines,” concludes Rehermann. Strategies to reverse this immune suppression should be examined.