David J. Barton

Associate Professor Ph.D., Medical College of Ohio

Current Research

My primary interests concern the molecular mechanisms of picornavirus replication and the evasion of interferon by hepatitis C virus.

Positive-strand RNA viruses like picornaviruses and hepatitis C virus are interesting because they replicate exclusively via RNA intermediates. Considering the “RNA World” view of the evolution of life, RNA viruses represent modern day organisms with evolutionarily ancient replication strategies. Positive-strand viral RNA serves two important functions within the cytoplasm of infected host cells:
(1) as mRNA for the expression of the viral proteins and,
(2) as the template for negative-strand RNA synthesis.
Viral RNA cannot simultaneously serve as a mRNA and as a template for negative-strand RNA synthesis due to the 5’ to 3’ movement of translating ribosomes on the viral mRNA and the 3’ to 5’ movement of replicase during negative-strand RNA synthesis. Communication between 5' and 3' terminal RNPs of viral RNA provides mechanisms to avoid ribosome-replicase collisions.

Poliovirus RNA, as mRNA, first becomes part of a messenger ribonucleoprotein (mRNP) complex with communication between the 5’- and 3’-termini mediated by the cellular translation machinery (eIF4G, poly (A) binding protein, poly (C) binding protein, etc.). Following viral protein synthesis, the viral mRNP complex must transform into a preinitiation RNA replication complex to allow for viral RNA replication. Poliovirus 2CATPase appears to mediate interactions between seemingly distal RNP complexes in poliovirus RNA to accomplish viral RNA replication. Our recently published model of poliovirus RNA replication (J. Virol. 2003), emphasizing communication between distally located RNP structures, is broadly applicable to all positive-strand RNA animal viruses.

In another series of experiments we discovered that hepatitis C virus RNA is detected and destroyed by an interferon-regulated antiviral pathway present in the cytoplasm of cells; the 2'-5' oligoadenylate synthetase/ribonuclease L pathway. Ribonuclease L cleaves viral RNA at single-stranded UA and UU dinucleotides. Relatively interferon-resistant genotype 1 hepatitis C viruses have fewer ribonuclease L cleavage sites than more interferon-sensitive genotype 2 and 3 viruses. These discoveries help to explain the clinical outcomes of interferon therapy in hepatitis C virus-infected patients where patients infected with genotype 1 viruses are cured less frequently by interferon therapy than patients infected with genotype 2 or 3 viruses.

Recent Publications

Click Here For An Updated List Of Dr. Barton's Recent Publications

Washenberger CL, Han JQ, Kechris KJ, Jha BK, Silverman RH, Barton DJ. Hepatitis C virus RNA: Dinucleotide frequencies and cleavage by RNase L. Virus Res. 2007 Jun 29;

Han JQ, Townsend HL, Jha BK, Paranjape JM, Silverman RH, Barton DJ. A phylogenetically conserved RNA structure in the poliovirus open reading frame inhibits the antiviral endoribonuclease RNase L. J Virol. 2007 Jun;81(11):5561-72.

Murray, K.E., B.P. Steil, A.W. Roberts, and D.J. Barton. 2004. Replication of poliovirus RNA with complete internal ribosome entry site deletions. J. Virol. 78: 1393-1402.

Han, J-Q, G. Wrobleski, Z. Xu, R. H. Silverman, and D.J. Barton. 2004. Sensitivity of hepatitis C virus mRNA to the antiviral enzyme ribonuclease L is determined by a subset of efficient cleavage sites. Journal of Interferon and Cytokine Research, 24:664-676.

Murray, K.E. and D.J. Barton. 2003. Poliovirus CRE-dependent VPg uridylylation is required for positive-strand RNA synthesis but not for negative-strand RNA synthesis. J. Virol. 8:4739-4750.

Barton, D.J., B.J. Morasco, L.E. Smerage and J.B. Flanegan. 2002. Poliovirus RNA replication and genetic complementation in cell-free reactions. In Wimmer, E., and Semler, B. (eds.) “Molecular Biology of Picornaviruses”. ASM Press, pgs. 461-469.

Han, J-Q, and D.J. Barton. 2002. Activation and evasion of the antiviral 2'-5' oligoadenylate synthetase/ribonuclease L pathway by hepatitis C virus. RNA 8:512-525.

Pathak, H.B., S.K.B. Ghosh, A.W. Roberts, S.D. Sharma, J.D. Yoder, J.J. Arnold, D.W. Gohara, D.J. Barton, A.V. Paul, and C.E. Cameron. 2002. Structure-function relationships of the RNA-dependent RNA polymerase from poliovirus (3DPol): A surface of the primary oligomerization domain functions in capsid precursor processing and VPg uridylylation. J. Biol. Chem. 277:31551-31562.

Barton, D.J., B.J. O'Donnell and J.B. Flanegan. 2001. 5' Cloverleaf in poliovirus RNA is a cis-acting replication element required for negative-strand synthesis. EMBO 20:1-10.

Murray, K.E., A.W. Roberts and D.J. Barton. 2001. Poly(rC) binding proteins mediate poliovirus RNA stability. RNA 7:1126-1141.

Lyons, T., K.E. Murray, A.W. Roberts and D.J. Barton. 2001. The 5' cloverleaf of poliovirus RNA is required for VPg uridylylation and the initiaiton of negative-strand RNA synthesis. J. Virol. 75:10696-10708.

Barton, D.J., B.J. Morasco and J.B. Flanegan. 1999. Translating ribosomes inhibit poliovirus negative-strand RNA synthesis. J. Virol. 73:10104-10112.

Barton, D.J. and J.B. Flanegan. 1997. Synchronous replication of poliovirus RNA: Initiation of negative-strand RNA synthesis requires the guanidine-inhibited activity of protein 2C. J. Virol. 71:8482-8489.