Research Synopsis: Crystallographic studies of hepatitis C viral proteins
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Structure and function of hepatitis C viral proteins
Hepatitis C virus (HCV) continues to be a major public health problem. In most cases, HCV infection becomes chronic and can persist for decades, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Currently, 3% of the human population is infected with HCV, making virus transmission a major public health concern. In the United States, HCV infection is the most common cause of liver transplantation and results in 10,000 to 20,000 deaths a year. There is no vaccine, and current HCV therapy, pegylated interferon-alpha in combination with ribavirin, leads to a sustained response in only 50% of genotype 1-infected patients, the prevalent genotype in the United States. There are numerous side effects, causing many patients to prematurely stop treatment. Given the high prevalence of infection and poor response rate, inhibitors that specifically target HCV proteins with fewer side effects are desperately needed. In addition, an effective vaccine would greatly reduce the spread of the virus.
HCV is a member of the family Flaviviridae, which also includes Pestiviruses and Flaviviruses. The HCV virion consists of an enveloped nucleocapsid containing the viral genome, a single-stranded, positive sense RNA that encodes a single open reading frame. Once the virus penetrates a permissive cell, the HCV genome is released into the cytosol where the viral RNA is translated in a cap-independent manner by an internal ribosome entry site (IRES) located within the 5' nontranslated region (NTR). Translation generates a viral polyprotein that is proteolytically processed by cellular and viral encoded proteases into ten proteins.
Our laboratory focuses on characterizing the structure and function of many of the HCV proteins and important cellular factors. We have determined the structure of two essential HCV proteins (NS2 and NS5A) by X-ray crystallography. The information gleaned from these studies was used to further define the function of these proteins. A better understand of the structure and function of the HCV proteins will contribute greatly to the current knowledge of HCV biology and aid in the design of novel therapies to combat HCV infection.
Khan AG, Miller MT, Marcotrigiano J. (2015) HCV glycoprotein structures: what to expect from the unexpected. Curr. Opin. Virol. 12:53-8
Khan AG, Whidby J, Miller MT, Scarborough H, Zatorski AV, Cygan A, Price AA, Yost SA, Bohannon CD, Jacob J, Grakoul A, Marcotrigiano J. (2014) Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509:381-4
Shin G, Yost SA, Miller MT, Elrod EJ, Grakoui A, Marcotrigiano J. (2012) Structural and functional insights into alphavirus polyprotein processing and pathogenesis. Proc. Natl. Acad. Sci. USA 109:16534-9
Jiang F, Ramanathan A, Miller MT, Tang GQ, Gale M Jr, Patel SS, Marcotrigiano J. (2011) Structural basis of RNA recognition and activation by innate immune receptor RIG-I. Nature 479:423-7
Whidby J, Mateu G, Scarborough H, Demeler B, Grakoui A, Marcotrigiano J. (2009) Blocking hepatitis C virus infection with recombinant form of envelope protein 2 ectodomain. J. Virol. 83:11078-89
Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr. (2008) Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454:523-7