Clinton Jones, Ph.D.

Professor, Charles Bessey Professorship
University of Nebraska-Lincoln
School of Veterinary and Biomedical Sciences
234 Morrison Center
Lincoln, NE 68583-0905
Phone - 402.472.1890
Fax - 402.472.3323
cjones@unlnotes.unl.edu

Current research activities

Latency of a-herpesvirinae subfamily members is the major focus of my research program.  We are studying two a-herpesvirinae subfamily members, Bovine Herpes Virus Type 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1), to identify common signaling pathways that regulate the latency-reactivation cycle. BHV-1 is a significant viral pathogen of cattle because it causes respiratory disease, abortion, occasionally encephalitis, and is a causative agent of Bovine Respiratory Complex, which costs the cattle industry more than $1 billion/year in losses/ year.  HSV-1 causes corneal blindness and encephalitis, and 25% of all new genital herpes cases.  BHV-1 and HSV-1 are important pathogens of their respective hosts. 

            a-herpesvirinae subfamily members initiate infection in mucosal epithelial surfaces located in the eye, nose, mouth, upper respiratory tract, or genital tract.  Extensive viral gene expression occurs, virus is shed, and clinical symptoms are apparent.  Virus then enters the peripheral nervous system, where it establishes a latent infection in sensory neurons.  Viral DNA can persist in a latent state for the lifetime of the infected host or can periodically reactivate.  In contrast to the 70-80 viral genes expressed in epithelial cells, viral gene expression is restricted in latently infected neurons.  The BHV-1 latency related (LR) gene and ORF-E, or the HSV-1 latency-associated transcript (LAT) are the only known viral genes that are abundantly expressed in latently infected neurons.  LAT and LR-RNA are transcribed from the opposite strand of an immediate early gene (ICP0) that encodes a protein, which stimulates productive infection and viral gene expression.  The latency-reactivation cycle can be operationally divided into 3 distinct stages: 1) establishment, 2) maintenance, and 3) reactivation form latency.  Reactivation from latency periodically occurs after a stressful stimulus and/or immune-suppression.  Successful reactivation leads to virus transmission and recurrent disease.  In summary, the latency-reactivation cycle of a-herpesvirinae subfamily members is crucial for pathogenesis and virus transmission.

            A protein, ORF2, encoded by the BHV-1 LR gene inhibits apoptosis.  ORF2 also interacts with important cellular transcription factors: Notch1, Notch3, and c/EBP-alpha.  ORF2 interferes with the ability of Notch1 to stimulate viral gene expression and productive infection.  Non-overlapping sequences in ORF2 are important for inhibiting apoptosis versus Notch functions.  Notch family members are crucial during embryogenesis, differentiation, and inappropriate expression enhances tumor cell growth.  Notch family members also interfere with neuronal differentiation, which ORF2 can block.  We recently discovered two micro-RNAs encoded within the LR gene.  These two micro-RNAs inhibit ICP0 expression, promote neuronal survival, and activate innate immune responses by interacting with the RNA sensor, RIG-I.

            Two small non-coding (snc)-RNAs encoded by HSV-1 LAT are expressed in latently infected sensory neurons.  These snc-RNAs inhibit apoptosis, interfere with ICP4 expression (a viral transcriptional activator required for productive infection), stimulate innate immune responses, and promote neuronal survival.  We also discovered a transcript (AL3) that is transcribed anti-sense with respect to LAT.  AL3 is expressed in the peripheral nervous system of mice latency infected with HSV-1, and AL3 encodes a protein.  In summary, LR gene products and LAT products regulate the latency-reactivation cycle.

            Reactivation from latency causes recurrent disease by HSV-1 and HSV-2, and is required for survival of all a-herpesvirinae subfamily members.  BHV-1 consistently reactivates from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone.  Calves latently infected with BHV-1 are being used to identify cellular and viral factors that are induced after dexamethasone-induced reactivation from latency. We have identified cellular transcription factors (PLZF, Slug, KLF family members, and SPDEF) that are activated by DEX.  These cellular transcription factors stimulate productive infection and certain viral promoters.  The viral bICP0 early promoter is strongly activated by these cellular transcription factors.  The bICP0 early promoter is also consistently activated during the early phases of reactivation from latency suggesting bICP0 promotes reactivation from latency.  Understanding the mechanism by which a-herpesvirinae subfamily members regulate the latency-reactivation cycle will lead to novel strategies for developing vaccines that protect against clinical disease, and inhibit reactivation from latency. 

 

Additional studies being pursued in the Jones laboratory include:

  • Analysis of stress-induced HSV-1 reactivation from latency: identification of cellular and viral factors that stimulate this process.
  • Regulation of innate immune responses and inflammation by BHV-1.

Development of BHV-1 modified live vaccines that do not reactivate from latency.

Selected Recent Publications


Sinani, D., L. Frizzo da Silva, and C. Jones.  2013.  A bovine herpesvirus 1 protein expressed in latently infected neurons (ORF2) promotes neurite sprouting in the presence of activated Notch1 or Notch3. J of Virology, 87:1183-1192.

Frizzo da Silva, L. and C. Jones.  Small non-coding RNAs encoded within the herpes simplex virus type 1 latency associated transcript (LAT) cooperate with the retinoic acid inducible gene I (RIG-I) to induce beta-interferon promoter activity and promote cell survival.  Virus Research, 175:101-109.

Jones, C.  2013.  Bovine herpesvirus 1 (BHV-1) and herpes simplex virus type 1 (HSV-1) promote survival of latently infected sensory neurons, in part by inhibiting apoptosis. J of Cell Death, 6:1-16.

Frizzo da Silva, L.  I. Kook, A. Doster, and C. Jones.  Bovine herpesvirus 1 regulatory proteins, bICP0 and VP16, are readily detected in trigeminal ganglionic neurons expressing the glucocorticoid receptor during the early stages of reactivation from latency. J of Virology, IN PRESS.

Devis Sinani, Ethan Cordes, Aspen Workman, Prasanth Thunuguntia, and Clinton Jones Stress-induced cellular transcription factors expressed in trigeminal ganglionic neurons stimulate the herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) promoter.  J of Virology, IN PRESS.

Brum. M.C.S., C. Coats, B.R. Sangena, A. Doster, C. Jones, and S.I. Chowdhury.  2009. Bovine herpesvirus type 1 (BoHV-1) anterograde neuronal transport from trigeminal ganglia to nose and eye requires glycoprotein E.  J. Neurovirology, 15:1-6.

Saira, K., Y. Zhou, and C. Jones.  2009.  The infected cell protein 0 encoded by bovine herpesvirus 1 (bICP0) associates with interferon regulatory factor 7 (IRF7), and consequently inhibits beta interferon promoter activity.  J. Virology. 83:3977-3981.

Meyer, F. and C. Jones. 2009.  C/EBP-alpha cooperates with bTIF to activate the bovine herpesvirus 1 immediate early transcription unit 1 promoter.  J. Neurovirology 15:123-130.

Jones, C. 2009.  Regulation of Innate Immune Responses by Bovine Herpesvirus 1 and Infected Cell Protein 0 (bICP0).  Viruses 1:255-275.

Workman, A., S. Perez, A. Doster, and C. Jones.  2009.  Dexamethasone treatment of calves latently infected with bovine herpesvirus 1 (BHV-1) leads to activation of the bICP0 early promoter, in part by the cellular transcription factor C/EBP-alpha. J. Virology, 83:8800-8809.

Jaber, T., G. Henderson, S. Li, G.-C. Perng, D. Carpenter, S. Wechsler, and C. Jones.  2009.  Identification of a novel herpes simplex virus type 1 (HSV-1) transcript and protein (AL3) expressed during latency.  J. Gen. Virology, 90: 2342 - 2352.

Shen, S., M. Sa e Silva, T. Jaber, O. Vitvitskaia, S. Li, G. Henderson, and C. Jones.  2009.  Two small RNAs encoded within the first 1.5 kb of the herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) can inhibit productive infection, and cooperate to inhibit apoptosis.  J. Virology, 83: 9131-9139.

Ellis, J., S. Gow, N. Goji, C. Jones, A. Workman, G. Henderson, G. Alaniz, and T. Meinert.  2009.  Efficacy of a combination viral vaccine in protecting cattle from experimental infection with bovine herpesviruses-1 isolated from recent “vaccine breaks”. J of American Veterinary Medical Association, 235:563-572.

Henderson, G., T. Jaber, D. Carpenter, S.L. Wechsler, and C. Jones.  2009.  Identification of herpes simplex virus type 1 proteins encoded within the first 1.5 kb of the latency-associated transcript.  J. of Neurovirology, 15: 479-488.

Beura L.K., S.N. Sarkar, B.J. Kwon, S. Subramaniam, C. Jones, A.K. Pattnaik, F.A. Osorio.  2010. Porcine reproductive and respiratory syndrome virus non-structural protein 1a modulates host innate immune response by antagonizing IRF3 activation.  J. Virology, 84: 1574-1584.

Li, S.,  D. Carpenter, C. Hsiang, S.L. Wechsler, and C. Jones. 2010.  The herpes simplex virus type 1 latency-associated transcript (LAT) inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels. J General Virology 91:858-866.

Jaber, T., A. Workman, and C. Jones. Small non-coding RNAs encoded within the bovine herpesvirus 1 latency related gene can reduce steady state levels of infected cell protein 0 (bICP0).  2010.  J Virology, 84: 6297–6307

Workman, A. and C. Jones.  Bovine herpesvirus 1 (BoHV1) productive infection and bICP0 early promoter activity are stimulated by E2F1. 2010. J Virology, 84: 6308–6317.

G.-C. Perng and C. Jones.  2010.  Towards an understanding of the Herpes Simplex Virus Type 1 latency-reactivation cycle. Interdisciplinary Perspectives on Infectious Diseases 2010:1-18.

Chowdhury, S. and C. Jones.  2010.  Bovine herpesvirus type 1 (BHV-1) is an important cofactor in the bovine respiratory disease complex. Veterinary Clinics of North America, Food Animal Practice, Bovine Respiratory Disease, eds V.L. Cooper and B. Broderson, 303-321.

Workman, A., D. Sinani, D. Pittayakhajonwut, and C. Jones.  2011.  A Protein (ORF2) Encoded by the Latency Related Gene of Bovine Herpesvirus 1 Interacts with Notch1 and Notch3. J Virology, 85: 2536-2546.

Jiang, X., A. Chentoufi , C. Hsiang, D. Carpenter, N. Osorio, L. BenMohamed, N.W. Fraser, C. Jones, and S.L. Wechsler.  2011.  The herpes simplex virus type 1 latency associated transcript (LAT) can protect cells from Granzyme B induced apoptosis and CD8 T-cell killing. J Virology 85:2325-2332.

Gaudreault, N. and C. Jones.  2011.  Regulation of promyelocytic leukemia (PML) protein levels and cell morphology by bovine herpesvirus 1 infected cell protein 0 (bICP0) and mutant bICP0 proteins that do not localize to the nucleus.  Virus Research, 156:17-24.

Allen, S.J., P. Hamrah, D.M. Gate, K.R. Mott, D. Mantopoulos, L. Zheng, T. Town, C. Jones, U. H. von Andrias ,G.J. Freeman, A.H. Sharpe, L. BenMohamed, R. Ahmed, S.L. Wechsler, and H. Ghiasi.  2011. The role of LAT in increased CD8+ T cell exhaustion 1 in trigeminal ganglia of mice latently infected with herpes simplex virus type 1.  J Virol, 85:4184-4197. 

Frizzo da Silva, L. and C. Jones. 2011. Infection of cultured bovine cells with bovine herpesvirus 1 (BHV-1) or Sendai virus induces different beta interferon subtypes.  Virus Research, 157: 54-60.

Workman, A. and C. Jones.  2011.  Analysis of the cell cycle regulatory protein (E2F1) after infection of cultured cells with bovine herpesvirus 1 (BHV-1) or herpes simplex virus type 1 (HSV-1).  Virus Research 160: 66-73.

Frizzo da Silva, L.F., N. Gaudreault, and C. Jones. 2011.  Cytoplasmic localized infected cell protein 0 (bICP0) encoded by bovine herpesvirus 1 inhibits beta interferon promoter activity and reduces IRF3 (interferon response factor 3) protein levels. Virus Research 169:143-149.

Chowdhury, S.I., M.C.S. Brum, C. Coats, A. Doster, H. Wei, C. Jones.  2011. Bovine Herpesvirus Type 1 envelope protein Us9 acidic domain is crucial for anterograde axonal transport.  Vet Micro 28:270-279.

Sinani, D. and C. Jones.  2011.  Localization of sequences in a protein encoded by the latency related gene of bovine herpesvirus 1 (ORF2) that inhibits apoptosis and interferes with Notch1 mediated trans-activation of the bICP0 promoter. J Virol 85: 12124-12133.

Jones, C., L.F. da Silva, and D. Sinani.  2011.  Regulation of the latency-reactivation cycle by products encoded by the bovine herpesvirus 1 (BHV-1) latency-related gene.  J Neurovirology, 17: 535-545.

Da Silva, L.F. and C. Jones. 2012.  Two micro-RNAs encoded within the BHV-1 latency related (LR) gene promote cell survival by interacting with RIG-I and stimulating nuclear factor-kappa B (NF-kB) dependent transcription and beta-interferon signaling pathways.  J Virol, 86:1670-1682.

Workman, A., J. Eudy, L. Smith, L. Frizzo da Silva, D. Sinani, H. Bricker, E. Cook, A. Doster, and C. Jones.  2012.  Cellular transcription factors induced in trigeminal ganglia during dexamethasone-induced reactivation from latency stimulate bovine herpesvirus 1 productive infection and certain viral promoters. J Virol 86: 2459-2473.

Frizzo da Silva, L., D. Sinani, and C. Jones. 2012.  The ICP27 protein encoded by bovine herpesvirus type 1 (bICP27) interferes with promoter activity of the bovine genes encoding beta interferon 1 (IFN-β1) and IFN-β3.  Virus Research, 169:162-168.

Sinani, D., L. Frizzo da Silva, and C. Jones.  2013.  A bovine herpesvirus 1 protein expressed in latently infected neurons (ORF2) promotes neurite sprouting in the presence of activated Notch1 or Notch3. J of Virology, 87:1183-1192.

Pittayakhajonwut, D., D. Sinani, and C. Jones.  2013.  A protein (ORF2) encoded by the latency related gene of bovine herpesvirus 1 interacts with DNA. J of Virology, 87: 5943-5501.

Jones, C.  2013.  Bovine herpesvirus 1 (BHV-1) and herpes simplex virus type 1 (HSV-1) promote survival of latently infected sensory neurons, in part by inhibiting apoptosis. J of Cell Death, 6:1-16.

Frizzo da Silva, L. and C. Jones.  Small non-coding RNAs encoded within the herpes simplex virus type 1 latency associated transcript (LAT) cooperate with the retinoic acid inducible gene I (RIG-I) to induce beta-interferon promoter activity and promote cell survival.  Virus Research, 175:101-109.

Frizzo da Silva, L.  I. Kook, A. Doster, and C. Jones.  Bovine herpesvirus 1 regulatory proteins, bICP0 and VP16, are readily detected in trigeminal ganglionic neurons expressing the glucocorticoid receptor during the early stages of reactivation from latency. J of Virology, IN PRESS.

Education

Bethany College, Lindsborg, KS
BA, Biology, Chemistry
1978

University of Kansas,
Lawrence, KS
PhD, Microbiology
1985

Linus Pauling Res. Inst.
Postdoc Fellow
1985-87

Professional Positions:

1996-
Professor: Dept of Veterinary & Biomedical Sciences
University of Nebraska-Lincoln, Lincoln, NE

1989-96
Associate Professor: Dept of Veterinary and Biomedical Sciences
University of Nebraska-Lincoln, Lincoln, NE

1987-89
Assistant Professor: Dept. of Microbiology
University of Mississippi Medical Center

1984-87
Post Doctoral Fellow: Laboratory of Viral Carcinogenesis
Linus Pauling Inst. of Science

Honors and Awards

  • Panel Manager for USDA Study Section (1996, 2001, 2004, and 2006)
  • Panel Member for USDA Study Section (1993, 1998, and 2011)
  • Outstanding Researcher, Gamma Sigma Delta (Honor Society of Agriculture), 2010
  • Editorial Board: Virology (2011-2015)
  • Editorial Board: World of Virology (2010-2015)
  • Editorial Board: PLOS One (2013-2018)
  • Study Section member for NIH, National Institute of Allergy and Infectious Diseases (NIAID).  Reviewed program project grants in 2010-2013.
  • Ad-Hoc Reviewer for NIH (2001 and 2003)