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Study highlights possible root of HCV persistence
January 2004, Volume 126, Number 1
The hepatitis C virus (HCV) causes a liver infection that resolves spontaneously in about 30% of humans. Spontaneous resolution of HCV infection usually affords long-term immunity to persistent viremia and associated liver diseases. However, the mechanisms responsible for the failure of infection to resolve have been unclear.
A study in the journal Science points to a possible explanation. Viruses that produce chronic infections such as hepatitis C may evade eradication by immune memory cells because the numbers of a required auxiliary immune cell dwindle over time. Dr. Arash Grakoui, postdoctoral fellow at Rockefeller University's Center for the Study of Hepatitis C, and colleagues report that an inadequate CD4+ T-lymphocyte response may be responsible for HCV persistence and immune evasion.
According to the authors, "the link between an effective CD4+ T-cell response and CD8+ T cell-mediated control of virus replication has been documented in several murine models of infection." While they add that these observations have yet to be extended to humans, HCV infection of chimpanzees provides "a highly relevant animal model to address this question."
Using a primate model of hepatitis C in their study, the researchers observed that antibody-mediated depletion of CD4+ T cells before reinfection in 2 immune chimpanzees resulted in persistent, low-level viremia despite functional intrahepatic memory CD8+ T-cell responses. In addition, the authors showed that incomplete control of HCV replication by memory CD8+ T cells in the absence of adequate CD4+ T-cell help was associated with emergence of viral escape mutations in class I major histocompatibility complex-restricted epitopes and failure to resolve HCV infection.
"Without sustained CD4+ T cell help, the CD8+ T cells "may not be able to keep pace with the evolution of viruses that rapidly accumulate escape mutations," say the authors.
"These observations may have implications for priming durable vaccine-mediated protection against HCV," the authors add. "Despite recent studies in mice showing good recall responses of memory CD8+ T cells without any requirement for help, our studies suggest that these cells alone will not afford protection for highly mutable viruses like HCV," they conclude.
For more details see Science 2003;302:659--662.
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