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INDIVIDUAL RESEARCHER

Kouacou V Konan , Ph.D.
Assistant Professor
e-mail: KonanK@mail.amc.edu

Phone: 518-262-9040

Education

1995 - Ph.D. from Indiana University


Current Research

The focus of my laboratory is to understand the mechanism of positive strand RNA virus genome replication and the transition from replication to virus particles formation. Our model system is hepatitis C virus (HCV), which remains a major public health concern despite the advent of direct-acting antivirals targeting HCV proteins. Approximately 4 million Americans are chronically infected with HCV, leading to chronic liver disease and more than 10,000 annual deaths.

 

HCV has evolved to co-opt host cytoplasmic membranes to build a unique replication platform called the membranous web (MW). The MW shelters and concentrates the HCV replication complex in distinct membrane domains for efficient genome replication. We have discovered that the host glycosphingolipids transport and biosynthetic proteins (e.g. four-phosphate adaptor protein 2 or FAPP2 and glucosylceramide synthase or GCS) are crucial for HCV RNA synthesis. For example, we have shown that FAPP2 depletion attenuates HCV infectivity and impedes HCV RNA synthesis. We also found that HCV significantly increases the level of some glycosphingolipids, whereas adding these lipids to FAPP2-depleted cells partially rescues replication, implying a requirement for glycosphingolipids in HCV RNA synthesis. Additionally, we have evidence that FAPP2 oligomerizes but the significance of FAPP2 quaternary structure in HCV RNA synthesis is unknown. Questions of interest include:

1. How does FAPP2 quaternary structure contribute to its function in HCV replication?

2. What are the role of FAPP2 domains in HCV replication?

3. How is FAPP2 recruited to the HCV replication complex?

4. Roles of sphingolipid biosynthetic proteins in HCV replication and virus-induced liver disease?

5. Can we utilize in vitro reconstitution to dissect the roles of FAPP2, and sphingolipids, in HCV replication?

 

In a complementary line of investigation, my laboratory is studying the mechanism whereby HCV nonstructural 4B (NS4B) protein organizes the virus replication complex and facilitates virus assembly. We have shown that HCV NS4B transmembrane domains (MSDs) are engaged in intra- and intermolecular interactions that are crucial for HCV replication. We have identified two protein-protein interaction motifs in these MSDs. These results raise the possibility that many NS4B protein-protein interactions could occur in the membrane bilayer and might be ideal targets for pharmacological intervention. Additionally, we have shown that NS4B facility HCV genome encapsidation by regulating the stability and/or phosphorylation state of HCV NS5A protein. Uncovering the host kinases or proteases as well as viral factors involved in HCV assembly will likely lead to better insight into the replication of HCV and related viruses.



PubMed Publications

  1. Influenza virus infection increases p53 activity: role of p53 in cell death and viral replication. Turpin, E, Luke K, Jones J, Tumpey T, Konan KV, and Schultz-Cherry S. 2005. J. Virol. 79, 8802-8811.


  2. Nonstructural protein precursor NS4A/B from hepatitis C virus alters function and ultrastructure of host secretory apparatus. Konan KV, Giddings TH Jr., Ikeda M, Li K, Lemon SM & Kirkegaard K. 2003. J. Virol. 77, 7843-7855.


  3. Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection.Guévin C, Manna D, Bélanger CM Sc., Konan KV, and Labonte P. 2010. Virol. 405, 1-7.


  4. Modulation of hepatitis C virus genome encapsidation by nonstructural protein 4B.Han Q, Manna D, Belton K, Cole R, and Konan KV. 2013. J. Virol. 87, 7409-7422.


  5. A human proteome microarray identifies that the heterogeneous nuclear ribonucleoprotein K (hnRNP K) recognizes the 5 ' terminal sequence of the hepatitis C virus RNA. Fan B, Lu KY, Sutandy FX, Chen YW, Konan KV, Zhu H, Kao CC, and Chen CS. 2013. Cell. Proteomics 13.1, 84-92.


  6. Lipids and RNA virus replication. Konan KV and Sanchez-Felipe L. 2014. Current Opinion in Virology 9, 45-52.


  7. Modulation of Hepatitis C Virus Genome Replication by Glycosphingolipids and Four-Phosphate Adaptor Protein 2. Khan I, Katikaneni DS, Han Q, Sanchez-Felipe L, Hanada K, Ambrose RL, Mackenzie JM, and Konan KV. 2014. J. Virol. 88, 12276-12295


  8. Participation of rab5, an early endosome protein, in hepatitis C virus RNA replication machinery. Stone M, Jia S, Heo WD, Meyer T, Konan KV. J Virol. 2007 May;81(9):4551-63. Epub 2007 Feb 14.


  9. Formation and function of hepatitis C virus replication complexes require residues in the carboxy-terminal domain of NS4B protein. Aligo J, Jia S, Manna D, Konan KV. Virology. 2009 Oct 10;393(1):68-83. Epub 2009 Aug 22.


  10. Bovine viral diarrhea virus NS4B protein is an integral membrane protein associated with Golgi markers and rearranged host membranes. Weiskircher E, Aligo J, Ning G, Konan KV. Virol J. 2009 Nov 3;6:185.


  11. Endocytic Rab proteins are required for hepatitis C virus replication complex formation. Manna D, Aligo J, Xu C, Park WS, Koc H, Heo WD, Konan KV. Virology. 2010 Mar 1;398(1):21-37. Epub 2009 Dec 16.


  12. Conserved GXXXG- and S/T-like motifs in the transmembrane domains of NS4B protein are required for hepatitis C virus replication. Han Q, Aligo J, Manna D, Belton K, Chintapalli SV, Hong Y, Patterson RL, van Rossum DB, Konan KV. J Virol. 2011 Jul;85(13):6464-79. Epub 2011 Apr 20.