Immune system homeostasis during acute hepatitis C: Viral escape or T-cell regulation?

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Immune System Homeostasis During Acute Hepatitis C: Viral Escape or T-Cell Regulation?

To the Editor:

We read with great interest the paper of Rahman et al. about the effects of antiviral therapy on the immune response during acute hepatitis C,1 and the conclusions of their investigation are fascinating.

Hepatitis C virus (HCV) is characterized by a high mutational capacity,2 so a continuous antigenic stimulus is directed at T lymphocytes. The ability to mount a vigorous and multispecific Th1 response is the key for disease resolution at an early phase3; on the other hand, the presence of an increased Th2 network could be related to progression to chronic disease.4 Over the last years, many studies have shown the importance of antigen specific CD4+ T cells to different epitopes in the natural history of HCV infection.5, 6 To provide a wider analysis and to understand the possible modulation of Th2 to Th1 network in early phase of infection, Rahman et al. have assayed the HCV-specific T-cell response toward 600 overlapping HCV peptides and 6 proteins by an ex vivo enzyme-linked immunospot. The authors hypothesized that a sustained response to the antiviral treatment was not associated with a lasting enhancement of HCV-specific T-cell responsiveness in blood. Moreover, they suggest that the impaired proliferative response could represent a possible adverse effect of interferon α.

In view of these results, we have some questions.

Is the absence of HCV-specific CD4+ T-cell enhancement related to sustained treatment in the periphery or a demonstration of immune system disease resolution response? In fact, during an infection, due to the homeostasis rules, when the antigenic stimulation ends, the CD4+ T-cell proliferation decreases.7 Thus, in the patients who had a sustained response and no viral load, the specific lymphocyte response could be suppressed probably and simply because it is no longer required. In contrast, when an antigen is not completely cleared, a T-cell immune response is still present. Indeed, this was the case in the study of 1 patient who developed a viral breakthrough while maintaining HCV-specific T-cell responses.

Concerning possible effects of interferon on T-cell proliferation, the proposed schedule of the authors includes ribavirin; this drug also exhibits some important effects on T lymphocytes, stimulating the Th1 network.8 In light of such evidence, how can they explain the antiproliferative and myelosuppresive effects of interferon without considering a possible influence of ribavirin too?

Moreover, an issue arises about the differences in HCV-specific T cells between the patients who resolve spontaneously and those who need treatment. Have the authors considered measuring possible inhibition mechanisms on HCV-specific T cells by means of other lymphocyte subsets, such as CD4+CD25+ (Treg) in their patients? Probably, the subjects without spontaneous viral clearance and illness resolution may exhibit an increased Treg lymphocytes percentage with inhibition of CD4+CD25 T cells, responsible for the immune response.

Finally, we think that the immune system homeostasis during acute HCV infection hides still-important data.

Alessandro Perrella*, Guglielmo Borgia*, Oreste Perrella†, * Department of Infectious Disease and Public Health, Federico II Medical School University, Naples, Italy, † Department of Infectious Disease and Immunology, Hospital D. Cotugno, Naples, Italy.

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