RESTORING HCV-SPECIFIC T CELL FUNCTIONS IN CHRONIC HEPATITIS C

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Funding source: NIDDK contract 263-MK-310378 Hepatitis C virus (HCV) poses a global health problem, because it readily establishes persistent infection and a vaccine is not available. The few patients who recovered spontaneously typically have vigorous CD4 and CD8 T cell responses. In chronic infection, however, HCV-specific T cell responses are typically weak. The reason for this weakness and so far, it has not been possible to strengthen the HCV-specific CD4 and CD8 T cell response therapeutically. Studying blood samples from a well characterized cohort of 16 chimpanzees, the sole animal model for HCV infection, we have previously demonstrated that CD4+ CD25+ T cells with regulatory functions in the blood of chimpanzees after HCV infection (Manigold T, Shin EC, Mizukoshi E, Mihal i(Ik Murthy K, Rice C, Piccirillo C, Rehermann B (2006), Blood, in press). These regulatory T cells expressed the characteristic transcription factor Foxp3 and suppressed proliferation and cytokine secretion of HCV-specific CD4 and CD8 T cells. Importantly, we were able to restore the proliferation and cytokine production of HCV-specific T cells by depleting the CD4+ CD25+ regulatory T cells from the chimpanzee blood samples (Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy K, Rice C, Piccirillo C, Rehemnn B (2006), Blood, in press). We now propose to deplete regulatory T cells in vivo from the blood of 3 chimpanzees with chronic infection. Based on a recent report (J Clin Invest 2005; 1 15: 3623) CD4+CD25+ T cells can be depleted with a single intravenous injection of recombinant IL2 diphtheria toxin conjugate DAB389IL2 (ONTAK, an FDA-approved drug, which has been used to treat cancer but not yet viral infections). We will first study the effect of a single intravenous injection of ONTAK and ask the question whether it depletes CD4+CD25+ T cells with regulatory function from the blood and the liver of the two HCV-infected chimpanzees and how long the effect lasts. If regulatory T cells can be depleted in chronic HCV infection, we will then give a second injection of ONTAK followed by HCV-specific vaccination. We will study the induction and function of HCV specific CD4 and CD8 T cells and their effect on HCV titer. We hypothesize that vaccination in the absence of CD4+CD25+ regulatory T cells may induce HCV clearance.