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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1408-1409.
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IMMUNOBIOLOGY
Comment on Schulze zur Wiesch et al, page 1559
CD4+ T cells don't always help
Christoph Neumann-Haefelin, and
Robert Thimme
UNIVERSITY HOSPITAL FREIBURG
In this issue of Blood, Schulze zur Wiesch and colleagues unmask strong CD4+ T-cell responses in some chronically HCV-infected patients as remainders of a previously resolved heterologous HCV infection rather than responses to the current persisting infection, further questioning protective immunity to heterologous HCV infection.
Increasing evidence suggests that the virus-specific CD4+ T-cell response plays a key role in the outcome of hepatitis C virus (HCV) infection. Consistent with this concept, individuals with resolved HCV infection harbor strong CD4+ T-cell responses against multiple CD4+ T-cell epitopes (patient 1 in the figure), whereas patients with persistent infection lack a significant CD4+ T-cell response (patient 2 in the figure).1,2 Strikingly, however, a subgroup of patients with persistent HCV non–genotype 1 infection shows a CD4+ T-cell response similar to individuals with resolved infection, when being studied with HCV genotype 1–derived peptides. These results led to the hypothesis that the CD4+ T-cell responses in these chronically HCV-infected patients may represent responses to a previous, resolved HCV genotype 1 infection rather than the current HCV non–genotype 1 infection (patient 3 in the figure).3,4 This hypothesis is supported in the elegant study by Schulze zur Wiesch and colleagues in this issue of Blood, which compares CD4+ T-cell responses in 24 patients with chronic HCV genotype 1 infection and 20 patients with chronic HCV non–genotype 1 infection using a full-breadth approach. Importantly, the large majority of CD4+ T-cell responses were detected in 4 HCV non–genotype 1 infected patients who were positive for HCV genotype 1–specific antibodies, indicating a previous, resolved HCV genotype 1 infection. In addition, these responses recognized peptides derived from HCV genotype 1, but not peptides derived from the autologous non–genotype 1 virus.
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Typical CD4+ T-cell responses in 3 patients with different courses of HCV infection. Patient 1 clears the virus in the presence of sustained vigorous and multispecific CD4+ T-cell responses. In patient 2, who has chronic HCV infection, CD4+ T-cell responses are hardly detectable. Patient 3 goes through acute, resolving HCV genotype 1 infection, resulting in sustained vigorous and multispecific CD4+ T-cell responses. Later, patient 3 is reinfected with a heterologous, HCV non–genotype 1 infection. The vigorous and multispecific CD4+ T-cell responses detectable in the patient represent remainders from the previous genotype 1 infection and do not prevent persistence of the HCV non–genotype 1 infection.
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These results extend previous observations in chimpanzees and smaller cohorts of patients, showing the absence of protection against a heterologous challenge. This study also provides the first evidence why a T-cell response induced by a previous resolved HCV infection may not confer protection against a heterologous challenge. Usually, individuals with resolved HCV infection target a number of immunodominant and highly conserved CD4 epitopes that are widely cross-reactive between different genotypes. The patients with heterologous reinfection identified in this study, however, target subdominant viral epitopes with high intergenotype variance. Thus, although genotype 1–specific T cells are detectable, these responses do not recognize peptides of the current, autologous HCV non–genotype 1 infection. Two different mechanisms could explain this interesting finding. First, the patients might have resolved the previous genotype 1 infection without targeting the usual immunodominat, cross-reactive CD4 epitopes. Second, and more tempting to assume, the reinfecting, heterologous HCV may evade the immune response by suppressing T-cell responses against these immunodominant, cross-reactive epitopes, while CD4+ responses against only weakly cross-reactive and thus irrelevant epitopes are sustained. This phenomenon has been called "antigenic sin" in other viral infections.
In sum, this study suggests that genotype 1–specific CD4+ T-cell responses do not confer protection against heterologous non–genotype 1 challenge. These results have important implications for vaccine development, because they suggest that the induction of promiscuous and broadly reactive CD4+ T-cell responses is required for protection from heterologous reinfection and that this does not necessarily occur during natural infection. Clearly, CD4+ T cells do not always help, especially if they only represent survivors of a previous battle.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Thimme R, Lohmann V, Weber F. A target on the move: innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res 2006; 69:129–141.[CrossRef][Medline]
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- Dustin LB and Rice CM. Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol 2007; 25:71–99.[CrossRef][Medline]
[Order article via Infotrieve]
- Sugimoto K, Kaplan DE, Ikeda F, et al. Strain-specific T-cell suppression and protective immunity in patients with chronic hepatitis C virus infection. J Virol 2005; 79:6976–6983.[Abstract/Free Full Text]
- Harcourt GC, Lucas M, Godkin AJ, Kantzanou M, Phillips RE, Klenerman P. Evidence for lack of cross-genotype protection of CD4+ T-cell responses during chronic hepatitis C virus infection. Clin Exp Immunol 2003; 131:122–129.[CrossRef][Medline]
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Related Article in Blood Online:
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Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non–genotype 1 infection
- Julian Schulze zur Wiesch, Georg M. Lauer, Joerg Timm, Thomas Kuntzen, Martin Neukamm, Andrew Berical, Andrea M. Jones, Brian E. Nolan, Steve A. Longworth, Victoria Kasprowicz, Cory McMahon, Alysse Wurcel, Ansgar W. Lohse, Lia L. Lewis-Ximenez, Raymond T. Chung, Arthur Y. Kim, Todd M. Allen, and Bruce D. Walker
Blood 2007 110: 1559-1569.
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