In accordance with NIHs decision to discontinue chimpanzee research we have completed and closed the corresponding animal protocols. Project 1: Innate and adaptive immune responses after low-dose exposure to HCV HCV-specific T-cell responses in the absence of viremia and HCV-specific antibodies have been observed in individuals who are thought to be frequently exposed to HCV antigens such as family members of HCV-infected patients (J Immunol. 1999;162:6681-9), health care workers (J Infect Dis. 2013;208:1020-5) and researchers (J Infect Dis. 1997;176:859-66) and a subpopulation of some injection drug users (J Infect Dis. 2008;198:203-12). It has been proposed that these T cell responses confer immune protection against HCV infection. We tested this hypothesis by repeatedly exposing chimpanzees to low amounts of HCV (human plasma or PBMC that tested positive for HCV by RT-PCR below the detection limit of the standard clinical assay at the NIH) and then challenging them with standard-dose HCV to assess protective immune responses. We found that HCV-specific T cells were induced in the low-dose HCV-exposed chimpanzees but not in a control chimpanzee exposed to plasma and PBMC from healthy blood donors. One of the low-dose HCV-exposed chimpanzees developed persistent viremia when HCV-specific T cell responses waned, the others maintained their T cell responses and remained aviremic. The immune profile of the aviremic chimpanzees was extensively characterized and was reminiscent of the immune status of subgroups of injection drug users, health care workers and family members of chronic HCV patients who are frequently exposed to low-level HCV but test HCV RNA and antibody negative. These chimpanzees were subsequently challenged with standard-dose HCV to assess the protective nature of these T cell responses in blood and liver. The experimental studies have been completed and the chimpanzees have been released from the protocol. The virological and immunological analyses of the preserved blood and liver biopsy samples are ongoing. Project 2: Immunotherapy of chronic HBV and HCV infection Although a vaccine exists to prevent new HBV infection, there is no cure for those patients who are already chronically infected. Antiviral treatment with nucleoside analogues that inhibit the viral reverse transcriptase does not eliminate HBV that persists in host cells in the form of closed circular DNA and continues to produce infectious virus. Continuous antiviral treatment is therefore necessary, and over years results in the selection of HBV escape mutants that render further treatment with antivirals ineffective. Chronic hepatitis, liver cirrhosis and hepatocellular carcinoma are the consequences. On the other hand, HBV can be cleared by the host immune response in the acute phase of infection and a very small percentage of patients (1%) is able to clear the virus spontaneously in the chronic phase. Spontaneous HBV clearance is mediated by vigorous T cell responses that recognize HBV-infected hepatocytes and either lyse them or cure them of HBV in an IFN-gamma-mediated manner. HBV-specific T cell responses and neutralizing antibodies then persist for decades and continue to exert immunosurveillance. In contrast, the number of HBV-specific T cells is low and their function is impaired in chronic infection. To date, it has not been possible to induce new, functional virus-specific T cells in chronic infection via vaccination or other measures. To test the hypothesis that successful HBV-specific T cell responses can be restored in chronic HBV infection, and to assess the fate of the adoptively transferred T cells in the liver, we have previously expressed a chimeric, antibody-based receptor (CAR) to HBsAg (Gastroenterology 2008;134:239-244) in blood lymphocytes from blood lymphocytes that were obtained from chimpanzees with chronic HBV infection. Upon transduction these lymphocytes gained a broad spectrum of HBV-specific effector functions (secretion of IFN-gamma, cytotoxicity and proliferation). After in vitro expansion to high numbers we have now infused them into chimpanzees with chronic HBV infection and obtained blood and liver biopsy samples to assess their effect on viral load and their fate in the liver. In parallel, chimpanzees with chronic HCV infection were treated with T cells that were transduced with T cell receptors from animals that successfully cleared HCV infection. As in HBV infection, a vigorous CD8 T cell response is required to spontaneously clear HCV and to maintain long-lasting protective immunity against reinfection. Blood and liver biopsy samples were obtained to assess the T cells effect on viral load and their fate in the liver. In a final part of the study, the response of the transferred HCV-specific T cells was boosted by administering a candidate vaccine. The experimental studies have been completed and the chimpanzees have been released from the protocol. The virological and immunological analyses of the preserved blood and liver biopsy samples are ongoing. Project 3: Identification of early immunological biomarkers for the outcome of HCV infection Using serial blood and liver biopsy samples from chimpanzees that had previously been infected with HCV genotype 1a several years ago (Major et al., Hepatology 2004;39:1709-1720) we investigated whether the outcome of HCV infection can be predicted early on by the phenotype of HCV-specific CD8+ T cells. CD8+ T cells are typically exhausted and overexpress inhibitory molecules in chronic HCV infection, but it is not known whether this is the cause or consequence of HCV persistence. To answer this question it is important to study very early time points after infection, when these T cells first appear in the blood and to also assess the immune response in the infected organ, the liver. In this project we demonstrated that the early expression of the memory precursor marker CD127 on HCV-specific T-cells, but not the expression of inhibitory molecules on those T-cells or their ligands in the liver, inhibitory cytokines or Tregs, predict the outcome of acute HCV infection. The experimental studies have been completed and the chimpanzees had already been released from the protocol years ago. The virological and immunological analyses of the preserved blood and liver biopsy samples have been completed.

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Didion, John P; Morgan, Andrew P; Yadgary, Liran et al. (2016) R2d2 Drives Selfish Sweeps in the House Mouse. Mol Biol Evol 33:1381-95
Holz, Lauren; Rehermann, Barbara (2015) T cell responses in hepatitis C virus infection: historical overview and goals for future research. Antiviral Res 114:96-105
Rehermann, Barbara; Bertoletti, Antonio (2014) Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology :
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Park, Su-Hyung; Veerapu, Naga Suresh; Shin, Eui-Cheol et al. (2013) Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection. Nat Med 19:1638-42
Rehermann, Barbara (2013) Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 19:859-68
Zu, Yao; Tong, Xiangjun; Wang, Zhanxiang et al. (2013) TALEN-mediated precise genome modification by homologous recombination in zebrafish. Nat Methods 10:329-31

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