William Halford

Summary

Affiliation: Southern Illinois University School of Medicine
Location: Springfield, IL
URL: http://www.siumed.edu/mmi/faculty/Halford/index.html
Summary:
Research Goals:

From a basic science viewpoint, Dr. Halford's research focuses on elucidating how key factors such as HSV's ICP0 protein and the host interferon response contribute to HSV's ability to "choose" between productive replication and non-productive infection each time the virus enters a new cell in vivo. For more information on this topic, see Chapter 5 of Viruses and Interferon: Current Research, 2011.
From the clinical viewpoint, the basic science described above suggests a simple and rational path that would yield a new class of HSV-2 vaccine. Specifically, interferon-sensitive HSV-2 ICP0- mutant viruses should be unable to cause disease in experimental animals or humans, but effectively prime the adaptive immune system such that the vaccine recipient is resistant to later exposures to wild-type HSV-2. Published work and ongoing experiments in the lab indicate that, in fact, live HSV-2 ICP0- mutant viruses are a viable strategy to obtain a safe and effective HSV-2 vaccine that renders vaccinated animals completely resistant to HSV-2 genital herpes. Work in the laboratory is currently focused on determining how effective these live HSV-2 vaccine strains are relative to three HSV-2 vaccine candidates that have previously advanced to human clinical trials; namely, 1. protein subunit vaccines such as Glaxo Smith Kline's Herpevac vaccine, 2. replication-defective HSV-2 viruses such as Sanofi Pasteur's ACAM-529 vaccine, and 3. live-attenuated HSV-2 viruses bearing mutations in 4 or more viral genes (Biovex's ImmunovexHSV-2 vaccine).

Updates on the status of research and development of Dr. Halford's live HSV-2 vaccine candidates may be found at http://herpesvaccineresearch.com/.
Grants:
1998 – 2000 The role of HSV-1 ICP0 in reactivation from latency, 1F32 AI10147. National Institutes of Health. Individual NRSA for W.P. Halford.
2001 – 2004 Vaccination against herpes simplex and human immunodeficiency virus using gene therapy vectors, LEQSF-RD-A-33. Louisiana Board of Regents Support Fund. P.I. Halford.
2002 – 2003 The role of the LAT-ICP0 locus in regulating HSV latency. 1R21 AI51414. National Institutes of Health. P.I. Halford.
2003 – 2007 The role of the LAT-ICP0 locus in regulating HSV latency. 1R01 AI51414. National Institutes of Health. P.I. Halford.
2008 - 2009 Development of an effective genital herpes vaccine. Central Research Committee, SIU School of Medicine. P.I. Halford.
2008 – 2009 Development of a live, immune-sensitive HSV-2 vaccine. Excellence in Academic Medicine Award, SIU School of Medicine. P.I. Halford.
2009 - 2011 Development of an effective genital herpes vaccine. R21 AI81072, National Institutes of Health. P.I. Halford.
2010 - 2011 Year 2 Supplement, “Development of an effective genital herpes vaccine” (R21 AI81072), National Institutes of Health. P.I. Halford.
2010 – 2011 A safe and effective genital herpes vaccine. Excellence in Academic Medicine Award, SIU School of Medicine. P.I. Halford.
2010 – 2011 A system for controlling gene expression in mammalian systems. Concept Development Award, SIU School of Medicine. P.I. Wilber.
Publications:
1. Halford, W.P., B.M. Gebhardt, and D.J.J. Carr. 1995. Functional role and sequence analysis of a lymphocyte orphan opioid receptor. J. Neuroimmunol. 59: 91-101.
2. Hill, J.M., W.P. Halford, R. Wen, L. Engel, L. Green, and B.M. Gebhardt. 1996. Quantitative analysis of polymerase chain reaction products by dot blot. Anal. Biochem. 235: 44-48.
3. Hill, J.M., B.M. Gebhardt, R. Wen, A. Bouterie, H. Thompson, R. O'Callaghan, W.P. Halford, and H.E. Kaufman. 1996. Quantitation of HSV-1 DNA and LAT in rabbit trigeminal ganglia demonstrates a stable reservoir of viral nucleic acids during latency. J. Virol. 70: 3137-3141.
4. Halford, W.P., B.M. Gebhardt, and D.J.J. Carr. 1996. Mechanisms of herpes simplex virus reactivation. J. Virol. 70: 5051-5060.
5. Halford, W.P., B.M. Gebhardt, and D.J.J. Carr. 1996. Persistent cytokine expression in trigeminal ganglion latently infected with herpes simplex virus-1. J. Immunol. 157: 3542-3549.
6. Halford, W.P., L. Veress, B.M. Gebhardt, and D.J.J. Carr. 1997. Innate and acquired immunity to herpes simplex virus type 1. Virology 236: 328-337.
7. Halford, W.P., B.M. Gebhardt, and D.J. Carr. 1997. Acyclovir blocks cytokine gene expression in trigeminal ganglion latently infected with herpes simplex virus. Virology 238: 53-63.
8. Halford, W.P., L. Veress, B.M. Gebhardt, and D.J.J. Carr. 1998. Immunization with HSV-1 antigen rapidly protects against HSV-1-induced encephalitis and is not dependent on interferon-. J. Interferon Cytokine Res. 18: 151-158.
9. Carr, D.J.J., W.P. Halford, L.Veress, S. Noisakran, G.-C. Perng, and S.L. Weschler. 1998. The persistent elevated cytokine mRNA levels in trigeminal ganglia of mice latently infected with HSV-1 are not due to the presence of latency associated transcript RNAs. Virus Res. 54: 1-8.
10. Noisakran, S., W.P. Halford, L. Veress, and D.J.J. Carr. 1998. The role of the hypothalamic-pituitary-adrenal axis and interleukin-6 in stress-induced reactivation of latent HSV-1. J. Immunol. 160: 5441-5447.
11. Carr,D.J.J., S. Noisakran, W.P. Halford, N. Lukacs, V. Asensio, and I.L. Campbell. 1998. Cytokine and chemokine production in HSV-1 latently infected trigeminal ganglion cell cultures: effects of hyperthermic stress. J. Neuroimmunol. 85: 111-121.
12. Halford, W.P., V.C. Falco, B.M. Gebhardt, and D.J.J. Carr. 1999. The inherent quantitative capacity of the reverse transcription-polymerase chain reaction. Anal. Biochem. 266: 181-191.
13. Halford, W.P. and P.A. Schaffer. 2000. Optimization of viral dose and transient immunosuppression enable herpes simplex virus ICP0-null mutants to establish wild-type levels of latency in vivo. J. Virol. 74: 5957-5967.
14. Halford, W.P. and P.A. Schaffer. 2001. ICP0 is required for the efficient reactivation of herpes simplex virus type 1 from neuronal latency. J. Virol. 75: 3240-3249.
15. Halford, W.P., C.D. Kemp, J.A. Isler, D.J. Davido, and P.A. Schaffer. 2001. ICP0, ICP4, or VP16 expressed from adenovirus vectors induces reactivation of latent herpes simplex virus type 1 in primary cultures of latently infected trigeminal ganglion cells. J.Virol. 75: 6143-6153.
16. Härle, P., B. Sainz, D.J.J. Carr, and W.P. Halford. 2002. The immediate-early protein, ICP0, is essential for the resistance of herpes simplex virus to interferon-/. Virology. 293: 295-304.
17. Al-khatib, K., R.H. Silverman, B.R.G. Williams, W.P. Halford, and D.J.J. Carr. 2002. Absence of PKR attenuates the anti-HSV-1 activity of an adenoviral vector expressing murine IFN-. J. Interferon Cytokine Res. 22: 861-871
18. Sainz, B. and W.P. Halford. 2002. Alpha/beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1. J. Virol. 76: 11541-11550.
19. Al-khatib, K., B.R.G. Williams, R.H. Silverman, W.P. Halford, and D.J.J. Carr. 2003. The murine dsRNA-dependent protein kinase PKR and the murine 2’,5’ oligoadenylate synthetase-dependent RNase L are required for IFN- mediated resistance against Herpes Simplex Virus Type 1 in primary trigeminal ganglion cultures. Virology. 313: 126-135.
20. Al-khatib, K., B.R.G. Williams, R.H. Silverman, W. Halford, and D.J.J. Carr. 2004. Distinctive roles for 2',5'-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-. J. Immunol. 172: 5638-5647.
21. Halford, W.P., J.W. Balliet, and B.M. Gebhardt. 2004. Re-evaluating natural resistance to herpes simplex virus type 1. J. Virol. 78: 10086 – 10095.
22. Al-khatib, K., B.R.G. Williams, R.H. Silverman, W. Halford, and D.J.J. Carr. 2005. Dichotomy between survival and lytic gene expression in RNase L- and PKR-deficient mice transduced with an adenoviral vector expressing murine IFN- following ocular HSV-1 infection. Exp. Eye Res. 80:167-173.
23. Soboleski, M.R., J. Oaks, and W.P. Halford. 2005. Green fluorescent protein is a quantitative reporter of promoter activity in individual eukaryotic cells. FASEB J. 19: 440-442.
24. Halford, W.P., K.J. Halford, and A.T. Pierce. 2005. Mathematical analysis demonstrates that interferons- and - interact in a multiplicative manner to disrupt herpes simplex virus replication. J. Theor. Biol. 234: 439-454.
25. Halford, W.P., J. L. Maender, and B.M. Gebhardt. 2005. Re-evaluating the role of natural killer cells in innate resistance to herpes simplex virus type 1. Virol. J. 2: 56.
26. A.T. Pierce, J. DeSalvo, T.P. Foster, A. Kosinski, S.K. Weller, and W.P. Halford. 2005. Beta-interferon and gamma interferon synergize to block viral DNA and virion synthesis in herpes simplex virus-infected cells. J. Gen. Virol. 86: 2421-2432.
27. Gebhardt, B.M. and W.P. Halford. 2005. Evidence that spontaneous reactivation of herpes virus does not occur in mice. Virol. J. 2: 67.
28. Austin, B.S., W. Halford, R.H. Silverman, B.R.G. Williams, and D.J.J. Carr. 2006. OAS and PKR are not required for the anti-viral effect of Ad:IFN-gamma against acute HSV-1 in primary trigeminal ganglia cultures. J Interferon Cytokine Res. 26: 220-225.
29. Halford, W.P., J. Grace, C. Weisend, M. Soboleski, D.J.J. Carr, J.W. Balliet, Y. Imai, T.P. Margolis, and B.M. Gebhardt. 2006. ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency. Virol. J. 3: 44.
30. Austin, B.A., W.P. Halford, B.R. Williams, and D.J. Carr. 2007. Oligoadenylate synthetase / protein kinase R pathways and /-TCR+ T cells are required for adenovirus vector: IFN- inhibition of herpes simplex virus-1 in cornea. J Immunol. 178: 5166-72.
31. Austin, B.A., W.P. Halford, P. Stuart, and D.J. Carr. 2009. Delivery of interferon- by an adenovirus vector Blocks HSV-1 reactivation in vitro and in vivo Independent of RNase L and dsRNA-dependent protein kinase pathways. J Neuroimmunol. 206: 39-43
32. Imai, Y, K. Apakupakul, P. R. Krause, W.P. Halford, and T. P. Margolis. 2009. Investigation of the mechanism by which HSV-1 LAT sequences modulate preferential establishment of latent infection in mouse trigeminal ganglia. J Virol. 83:7873-7882.
33. Liu, M., B. Rakowski, C.M. Weisend O. Lucas, E.E. Schmidt, and W.P. Halford. 2010. ICP0 antagonizes ICP4-dependent repression of the HSV ICP0 gene. PLoS ONE: 5(1): e8837.
34. Liu, M., E.E. Schmidt, and W.P. Halford. 2010. ICP0 dismantles microtubule networks in herpes simplex virus-infected cells. PLoS ONE: 5(6): e10975.
35. Halford, W.P., R. Püschel, and B. Rakowski. 2010. Herpes simplex virus 2 ICP0- mutants are avirulent and immunogenic: implications for a genital herpes vaccine. PLoS ONE 5(8): e12251.
36. Conrady, C.D., W.P. Halford, and D.J.J. Carr. 2011. The Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital HSV-2 Infection. J. Virol. 85: 1625 - 1633.
37. Halford, W.P., R. Püschel, E. Gershburg, A. Wilber, S. Gershburg, and B. Rakowski. 2011. A live-attenuated HSV-2 ICP0- virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine. PLoS ONE: 6(3):e17748.

Publications

  1. ncbi Functional role and sequence analysis of a lymphocyte orphan opioid receptor
    W P Halford
    Department of Microbiology, LSU Medical Center, New Orleans 70112 1393, USA
    J Neuroimmunol 59:91-101. 1995
  2. pmc A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 6:e17748. 2011
  3. pmc ICP0 dismantles microtubule networks in herpes simplex virus-infected cells
    Mingyu Liu
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA
    PLoS ONE 5:e10975. 2010
  4. pmc ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency
    William P Halford
    Dept of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA
    Virol J 3:44. 2006
  5. pmc Evidence that spontaneous reactivation of herpes virus does not occur in mice
    Bryan M Gebhardt
    LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    Virol J 2:67. 2005
  6. pmc Beta interferon and gamma interferon synergize to block viral DNA and virion synthesis in herpes simplex virus-infected cells
    Amy T Pierce
    Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA 70112, USA
    J Gen Virol 86:2421-32. 2005
  7. pmc Re-evaluating the role of natural killer cells in innate resistance to herpes simplex virus type 1
    William P Halford
    Dept of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA
    Virol J 2:56. 2005
  8. pmc Re-evaluating natural resistance to herpes simplex virus type 1
    William P Halford
    Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA
    J Virol 78:10086-95. 2004
  9. pmc Alpha/Beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1
    Bruno Sainz
    Department of Microbiology and Immunology, Tulane University Health Sciences Center, Program in Molecular Pathogenesis and Immunity, New Orleans, Louisiana 70112, USA
    J Virol 76:11541-50. 2002
  10. pmc ICP0, ICP4, or VP16 expressed from adenovirus vectors induces reactivation of latent herpes simplex virus type 1 in primary cultures of latently infected trigeminal ganglion cells
    W P Halford
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    J Virol 75:6143-53. 2001

Collaborators

Detail Information

Publications15

  1. ncbi Functional role and sequence analysis of a lymphocyte orphan opioid receptor
    W P Halford
    Department of Microbiology, LSU Medical Center, New Orleans 70112 1393, USA
    J Neuroimmunol 59:91-101. 1995
    ..Our results provide direct evidence that lymphocytes express an opioid-like receptor gene, and suggest that this receptor plays a functional role in immunocompetence...
  2. pmc A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 6:e17748. 2011
    ..Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if it contained a live-attenuated HSV-2 virus rather than a single HSV-2 protein...
  3. pmc ICP0 dismantles microtubule networks in herpes simplex virus-infected cells
    Mingyu Liu
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA
    PLoS ONE 5:e10975. 2010
    ....
  4. pmc ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency
    William P Halford
    Dept of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA
    Virol J 3:44. 2006
    ....
  5. pmc Evidence that spontaneous reactivation of herpes virus does not occur in mice
    Bryan M Gebhardt
    LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    Virol J 2:67. 2005
    ..The goal of this study was to differentiate between viral gene expression during latency and the episodic production of infectious virus in mice...
  6. pmc Beta interferon and gamma interferon synergize to block viral DNA and virion synthesis in herpes simplex virus-infected cells
    Amy T Pierce
    Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA 70112, USA
    J Gen Virol 86:2421-32. 2005
    ..It was inferred that IFN-mediated suppression of HSV-1 replication may be a central mechanism by which the host immune system limits the spread of HSV-1 infection in vivo...
  7. pmc Re-evaluating the role of natural killer cells in innate resistance to herpes simplex virus type 1
    William P Halford
    Dept of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA
    Virol J 2:56. 2005
    ..The current study was initiated to determine if natural killer (NK) cells provide innate resistance to HSV-1 infection, and if so to determine if this resistance is IFN-gamma-dependent...
  8. pmc Re-evaluating natural resistance to herpes simplex virus type 1
    William P Halford
    Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA
    J Virol 78:10086-95. 2004
    ....
  9. pmc Alpha/Beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1
    Bruno Sainz
    Department of Microbiology and Immunology, Tulane University Health Sciences Center, Program in Molecular Pathogenesis and Immunity, New Orleans, Louisiana 70112, USA
    J Virol 76:11541-50. 2002
    ..Because IFN-alpha or IFN-beta is produced by most cells as an innate response to virus infection, the results imply that IFN-gamma secreted by T cells may provide a critical second signal that potently inhibits HSV-1 replication in vivo...
  10. pmc ICP0, ICP4, or VP16 expressed from adenovirus vectors induces reactivation of latent herpes simplex virus type 1 in primary cultures of latently infected trigeminal ganglion cells
    W P Halford
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    J Virol 75:6143-53. 2001
    ..We conclude that this system provides a powerful tool for determining which cellular and viral proteins are sufficient to induce HSV-1 reactivation from neuronal latency...
  11. ncbi The inherent quantitative capacity of the reverse transcription-polymerase chain reaction
    W P Halford
    Department of Microbiology, University of Pennsylvania, 221 Johnson Pavilion, Philadelphia, Pennsylvania, 19104 6076, USA
    Anal Biochem 266:181-91. 1999
    ..Thus, with statistically adequate sample numbers, an appropriate standard curve, and the inherent quantitative capacity of the method, differences in the abundance of a mRNA species are measurable by 35-cycle RT-PCR...
  12. ncbi Cytokine and chemokine production in HSV-1 latently infected trigeminal ganglion cell cultures: effects of hyperthermic stress
    D J Carr
    Department of Microbiology, Immunology and Parasitology, LSU Medical Center, New Orleans, LA 70112 1393, USA
    J Neuroimmunol 85:111-21. 1998
    ....
  13. pmc HSV-1 latent rabbits shed viral DNA into their saliva
    James M Hill
    Department of Ophthalmology LSUHSC School of Medicine, 533 Bolivar Street, Room 3D13, New Orleans, LA 70112, USA
    Virol J 9:221. 2012
    ..This study used real-time PCR to quantify HSV-1 DNA in the saliva and tears of rabbits latent with HSV-1 McKrae...
  14. pmc Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 8:e65523. 2013
    ..Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes...
  15. pmc Herpes simplex virus 2 ICP0 mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 5:e12251. 2010
    ..Based on their avirulence and immunogenicity, we propose that HSV-2 ICP0(-) mutant viruses merit consideration for their potential to prevent the spread of HSV-2 and genital herpes...