Susan L. Uprichard, PhD
Director of Hepatology Research
Ph.D. in Virology, Harvard University
Research Interest: Although hepatitis viruses represent a significant public health burden, research efforts to understand these infections have been hindered by the lack of experimental model systems. For this reason, the focus of our laboratory is the development and utilization of experimental systems and mathematical models needed to dissect the life cycle of these viruses, understand and optimize treatment response, elucidate the molecular mechanisms of virus-associated liver disease (e.g. steatosis and hepatocellular carcinoma), and identify the viral-host interactions that determine the outcome of infection.
Hepatitis C Virus (HCV). Based on our success establishing the first infectious HCV cell culture system, it is now possible to study the viral-host interactions that mediate HCV entry and cell-to-cell viral spread. We have identified two new HCV entry factors (one of which is also required for cell-to-cell spread) and are interested to determine how these and other factors function, affect infection dynamics and their therapeutic potential as antiviral drug targets. While viral entry inhibitors are generally not screened for their ability to block viral cell-to-cell spread, our data suggests that blocking cell-to-cell spread is critical for optimal drug synergy and limiting viral escape. By mathematically modeling of viral spread and HCV treatment response in vitro and in vivo (in mice with humanized livers and patients) clinically relevant direct acting antivirals (DAAs), we hope to optimize, shorten, and reduce pricing of HCV treatment so that it becomes more readily accessible to all those infected. In addition, as small animal models are still needed to elucidate the critical viral-host interactions that determine how the virus induces the HCV-associated liver pathology, such as hepatocellular carcinoma, we are also interested in developing mouse models of HCV infection. We have already shown that the JFH-1 HCV viral clone can replicate in mouse hepatocytes and recently identified an HCV entry factor, Neimann Pick C1 Like-1 (NPC1L1), which is uniquely expressed on human and chimpanzee hepatocytes and thus mimics the species tropism of HCV. We are currently investigating if expression of NPC1L1 on mouse hepatocytes can mediate infectious HCV entry.
Hepatitis B Virus (HBV). The recent discovery of the HBV entry receptor, the Na+-taurocholate cotransporting polypeptide (NTCP), has opened the door for the development of robust HBV infection models. While it has been demonstrated that NTCP confers cellular permissiveness to HBV infection, the replication levels achieved were suboptimal. Because HBV gene expression, and thus subsequent replication, is depended on hepatocyte-specific transcription factors, we are testing permissiveness of more physiologically relevant hepatocyte cell culture methods to create a more robust HBV infection system that would permit for the first time the study of the authentic HBV cccDNA-driven life cycle and antiviral strategies targeting the stable cccDNA molecule that currently thwarts HBV treatment efforts.
Canini, L., H. Dahari, X. Zhao, S.L. Uprichard, V. Haynes-Williams, M.A. Winters, G. Subramanya, S.L. Cooper, P. Pinto, E.F. Wolff, R. Bishop, M.A. Thanda Han, S.J. Cotler, D.E. Kleiner, O. Keskin, R. Idilman, C. Yurdaydin, J.S. Glenn, T. Heller and C. Koh (2015) Oral Prenylation Inhibition with Lonafarnib in Chronic Hepatitis D Infection: a randomized, double-blinded, placebo controlled phase 2a trial. The Lancet Infectious Diseases (in press).
Graw, F., D.N. Martin, A.S. Perelson, S.L. Uprichard, H. Dahari (2015) Quantification of HCV cell-to-cell spread using a stochastic modeling approach. Journal of Virology 89(13):6551-61.
Uprichard, S.L. and B. Sainz Jr. (2014) Inhibition of hepatitis C entry: too soon to dismiss while many are still being denied treatment. Gut 64(4):690-1.
Barretto, N, B. Sainz, Jr., S. Hussein, and S.L. Uprichard (2014) Determining the involvement of host cellular factors in HCV cell-to-cell spread and the therapeutic implications. Journal of Virology 88(9):5050-61.
Martin, D.M. and S.L. Uprichard (2013) Identification of Transferrin Receptor 1 as a Hepatitis C Virus entry factor. Proc Natl Acad Sci U S A. 110(26):10777-82.
Guedja J, H. Dahari, L. Rong, N.D. Sansone, R.E. Nettles, S.J. Cotler, T.J. Layden, S.L. Uprichard and A.S. Perelson (2013) Modeling shows that NS5A inhibitor daclatasvir has two modes of action and yields a revised estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A. 110:3991-6.
Yu X, B. Sainz Jr, P.A. Petukhov, and S.L. Uprichard (2012) Identification of HCV Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay. Antimicrob Agents Chemother. 56:6109-20.
Sainz, B. Jr., N. Barretto, D.N. Martin, N. Hiraga, M. Imamura, K.A. Marsh, X.Yu, S. Hussain, K.Chayama, W.A. Alrefai, and S.L. Uprichard (2012) The Niemann-Pick C1-Like 1 cholesterol absorption receptor: a novel hepatitis C virus entry factor and therapeutic target. Nature Medicine 18(2):281-5.
Yu X, B. Sainz Jr., S.L. Uprichard (2009) Development of a cell-based hepatitis C virus infection fluorescent resonance energy transfer assay for high-throughput antiviral compound screening. Antimicrob Agents Chemother. 53(10):4311-9.
Zhong, J., P. Gastaminza, G. Cheng, S. Kapadia, T. Kato, D.R. Burton, S.F. Wieland, S.L. Uprichard, T. Wakita, F.V. Chisari (2005) Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A. 102(26):9294-9299.
Uprichard S.L., B. Boyd, A. Althage, F.V. Chisari (2005) Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):773-8.