Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells
Authors: Michelina Nascimbeni, Thomas Montange, Helen K. W. Law, Vincent Mallet, Bertrand Saunier, Yves Rivière, Stanislas Pol
Journal: Hepatology (2009)

Reply: We were highly interested in the study by Kottilil et al.,1 which reported the existence of distinct immunologic imprints in peripheral blood mononuclear cells (PBMCs) of patients chronically monoinfected with hepatitis C virus (HCV) and and those chronically coinfected with HCV/human immunodeficiency virus (HIV), compared to HIV-monoinfected or noninfected individuals. In addition, interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) proinflammatory cytokines were found within a cluster of genes significantly up-regulated only in the group of HCV-monoinfected individuals, and were also measured by enzyme-linked immunosorbent assay in the supernatants of cultured PBMCs. We have had the opportunity to study the PBMCs of five patients monoinfected with HCV and five patients coinfected with HIV/HCV at the acute phase of the HCV infection (<4 months from the date of contamination) and before antiviral treatment. The T cell proliferative response to (HCV) NS3 or (HIV) gag (overlapping 15-unit oligomers), CEF (cytomegalovirus, Epstein-Barr virus, and flu virus) peptide mix or tetanus toxoid (TT) was investigated, and the production of cytokines in response to the same antigens as well as staphylococcus enterotoxin B (SEB) was measured in the supernatants of PBMCs in culture. In the T cell proliferation assay, a response to at least one antigen was observed for five patients: four in the HCV group and one in the HIV/HCV-coinfected group. The latter patient only responded to HIV gag peptide pool, i.e., not to HCV NS3. In the HCV group, one patient responded to NS3, and none responded to gag. Interestingly, the production of IL-8 was already high and not responsive to the antigens; however, patterns were identical in monoinfected and coinfected patients (not shown). At variance with IL-8 (Fig. 1), no TNF-α production was detected without antigenic stimulation. An increased TNF-α production by PBMCs of HCV-monoinfected patients was observed in response to NS3, CEF, TT, and SEB, whereas those of HCV/HIV-coinfected ones only responded to gag, CEF, TT, and SEB, i.e., surprisingly not to NS3. Production of TNF-α by PBMCs isolated from patients at the acute phase of HCV infection. After 6-day stimulation2 with the indicated antigens, TNF-α immunoreactivity was measured in culture supernatants using xMAP technology (Luminex, Austin, TX); error bars represent standard error of the mean. The fact that patients coinfected with HIV/HCV failed to respond to the pool of NS3 peptides whereas patients monoinfected with HCV did was a trend also observed with the production of other cytokines, including interferon-γ, interferon-inducible protein-10/chemokin (C-X-C motif) ligand 10 (CXCL10), macrophage inflammatory protein-1α/chemokine (C-C motif) ligand 3, and MIG/CXCL9 (not shown). For several cytokines, productions in response to other antigens were similar in both groups, which did not support the hypothesis that globally impaired immune responses in HIV/HCV-coinfected patients explained the lack of anti-HCV immune response in vitro. These results outline the discrepancies existing between PBMCs at the acute phase of HCV infection (as in the present results) and its chronic stage,1 in both HCV-monoinfected and HCV/HIV-coinfected patients. They additionally suggest that patients with HIV who more rapidly develop liver complications when coinfected with HCV could be the consequence of a specific defect of their cellular response to HCV antigens at the acute phase of infection. Michelina Nascimbeni*, Thomas Montange , Helen K. W. Law , Vincent Mallet* §, Bertrand Saunier*, Yves Rivière , Stanislas Pol* §, * Hepatitis C Virus Laboratory, Department of Immunology, Institut Cochin, Institut National de la Santé et de la Recherche Meédicale U567, Centre National de la Recherche Scientifique (CNRS) UMR8104, Paris-Descartes University, Paris, France, Laboratory of Viral Immune Pathology, CNRS URA3015, Paris, France, Center of Human Immunology, Department of Immunology, Institut Pasteur, Paris, France, § Hepatology Unit, Department of Hepato-Gastroenterology, Cochin Hospital, Paris, France.