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Item Durability of Response in Children Treated with Pegylated Interferon alfa-2a +/- Ribavirin for Chronic Hepatitis C(Lippincott Williams & Wilkins, 2016-01) Schwarz, Kathleen B.; Molleston, Jean P.; Jonas, Maureen M.; Wen, Jessica; Murray, Karen F.; Rosenthal, Philip; Gonzalez-Peralta, Regino P.; Lobritto, Steven J.; Mogul, Douglas; Pavlovic, Vedran; Warne, Charles; Wat, Cynthia; Thompson, Bruce; Department of Pediatrics, IU School of MedicineObjectives: No long-term data have been published on the durability of response following pegylated interferon (PegIFN) treatment in children with chronic hepatitis C. This prospective, multicenter, long-term follow-up (LTFU) study aimed to assess long-term durability of sustained virological response (SVR), long-term safety and tolerability, and the association between IL28B genotype and treatment response, in children previously treated with PegIFN alfa-2a ± ribavirin (RBV) in the PEDS-C trial. Methods: A total of 93 patients were assessed for enrollment, and 38 enrolled in the study. Patients attended 2 study visits: 5 (mean 5.6, range 4.1–6.6) and 6 (6.6, 5.1–7.7) years after treatment cessation. Standardized medical history, physical examination, and laboratory testing were performed at these visits. Reminder telephone calls were conducted at 4 and 8 months after the initial visit. Results: The LTFU cohort was the representative of the original PEDS-C cohort because both baseline and treatment characteristics were comparable. Of the 38 participants, 21 achieved SVR (responders) during the PEDS-C trial and 17 had not (nonresponders). All 21 responders maintained undetectable hepatitis C virus RNA during the LTFU (4.4–7.0 years after achieving SVR) in contrast to the nonresponders who demonstrated persistent viremia. IL28B CC genotype was associated with SVR (67% vs 30% in non-CC, P = 0.028). Conclusion: Long-term durability of SVR is excellent following PegIFN alfa-2a treatment in children with chronic hepatitis C; SVR is higher in those with IL28B CC versus non-CC.Item THE ROLE OF THE VIRAL NEF PROTEIN AS A MEDIATOR OF HIV-1 INDUCED ENDOTHELIAL DYSFUNTION(Office of the Vice Chancellor for Research, 2012-04-13) Wang, Ting; Green, Linden; Clauss, MatthiasWith the prevalence of antiviral therapy in the developed world, many HIV-1-infected people die of diseases other than AIDS. One of the emerging major causes is cardiovascular disease, leading to the prediction that the majority of HIV-1 patients are expected to develop cardiovascular complications. Endothelial dysfunction is thought to be a key event in the development of cardiovascular diseases, particular-ly atherosclerosis. Assays testing the effect of HIV-1 on endothelial ac-tivation shows that direct contact with HIV-1 infected T cells enhance endothelial cell activation to a greater extent than HIV-1 alone, sug-gesting an intracellular HIV-1 protein is responsible for endothelial ac-tivation. The HIV-1 viral protein Nef, which is responsible for T cell ac-tivation and maintenance of high viral loads in vivo, has been shown to mediate its own transfer to bystander cells. We demonstrate here for the first time that Nef induces nanotube-like conduits connecting T cells and endothelial cells. We also show that Nef is transferred from T cells to endothelial cells via these nanotubes, and is necessary and sufficient for endothelial cell activation. Moreover, we show that SIV-infected macaques exhibit endothelial Nef expression in coronary ar-teries. Nef expression in endothelial cells causes endothelial apoptosis, ROS and MCP-1 production. Interestingly, a Nef SH3 binding site mu-tant abolishes Nef-induced apoptosis and ROS formation and reduces MCP-1 production in endothelial cells, suggesting that the Nef SH3 binding site is critical for Nef effects on endothelial cells. Nef induces apoptosis of endothelial cells through an NADPH oxidase- and ROS-dependent mechanism, while Nef-induced MCP-1 production is NF-kB dependent. Taken together, these data suggest that Nef can mediate its transfer from T cells to endothelial cells through nanotubes to en-hance endothelial dysfunction in vivo. Thus, Nef is a promising new therapeutic target for reducing the risk for cardiovascular disease in the HIV-1 positive population.