Paul (Kip) R. Kinchington, PhD

  • Joseph F. Novak, M.D., Chair in Ophthalmology Research
  • Professor of Ophthalmology, Molecular Genetics and Biochemistry
  • The Campbell Laboratory for Infectious Eye Diseases
  • University of Pittsburgh School of Medicine

A Conversation With Dr. Kinchington

I have long been interested in viruses that cause blinding infections in the eye, which is why I join the Department of Ophthalmology at Pitt in 1991.  As a teen, I had a close friend who lost much of his vision due to an ocular herpesvirus infection.  Given my research training was in the molecular biology of herpesviruses, I simply put the two together for my research career, which I have enjoyed since then.   Herpesviruses are common viruses in the human population with a facinating ability to switch between two types of infection:- one is to make more virus, while the other is to persist in the host for life in a quiet, dormant “latent” state, where there is no virus made, but the viral genome is maintained in a state that is largely invisible to immunity.  This can then sporadically reawaken to make virus, inflict disease, cause damage and spread to new hosts.  The eye is particularly susceptible to some of these viruses, particularly Herpes Simplex virus type 1 (HSV-1, which commonly causes cold sores): and Varicella zoster virus (VZV), which causes chickenpox,  and the painful disease common to the elderly and immune impaired known as Herpes Zoster (or Shingles).  In the infected eye, they can cloud the cornea, destroy the retina, and induce neuropathic ocular diseases ranging from serious ocular pain, irritation and unwanted eye movements, to loss of corneal sensation and partial and even total loss of vision, which of course will greatly affect one’s quality of life.  While I was trained as a molecular virologist, I felt the opportunity was ripe to study virology with ophthalmology in my research.  

Collaborative Research   I came to Pitt because there was a huge and exciting opportunity to collaborate in scientific research.  Colleagues and other Investigators were always willing to shoot around ideas, discuss novel concepts, or help take a project in a new direction.  I have been at Pitt for 33 years.  I have also had the opportunity to collaborate with vision researchers through directing a “Molecular Biology module” of an NEI funded Center of Research Excellence (CORE) NIH award we have had for 30+ years.  Our module provides technical expertise to vision researchers who might not have the needed skills or resources to do molecular biology.  There are other modules that help with qualtitative imaging, histology, tissue culture, flow cytometry and fabrication of “Widgets”. Our module is particularly skilled in making multiple viruses for use as vectors that can deliver genes or modulate the expression of a host protein in order to identify it’s functions.  All these modules have permited many NEI-funded researchers and Investigators to advance their programs in ways that might not have happened otherwise.

What is our group researching into?  Currently, most of our work addressing VZV, a virus that can infect and cause disease in virtually any part of the eye.  The virus itself is quite difficult to work with: outside of humans, it does not grow well in culture, which is largely restricted to human cells, and progeny virus remains tightly associated to the producing cell.   It’s human specificity precludes the use of small animal modeling of eye infection, disease and pathogenesis. Indeed, I am one of a small number of researchers with the expertise to grow, manipulate and study this virus’s biology.  

We have three VZV projects going on in the lab. The first is to understand why VZV causes debilitating pain, which is a frequent and serious complication of Herpes Zoster in humans. We developed a footpad pain model, and now have an exciting new facial pain model that mimics aspects of the ocular pain that develops in many facial shingles patients.  These models are not only used to examine underlying mechanisms, but also evaluate new pain-relieving treatments.  The second VZV project is to understand how the virus infects and maintains itself in sensory neurons for decades, only to reawaken and cause Shingles.  We are investigating the functions of the RNAs made during the latent state and if they contribute to gene silencing.  What are the triggers of reactivation?  Can these be targeted to prevent virus reactivation and shingles? To study these topic, we developed a new cultured human neuron system that mimics the interactions of virus and nerve cells in dishes. For example, we are trying to remove the latent virus from neurons using CRSPR-cas9 systems.  Finally, Our third VZV project aims to understand why the live virus VZV vaccine is attenuated for growth in human skin and neurons.  The vaccine virus contains hundreds of genome changes compared to a wild type virus, in different combinations and mixes. We study these mutations a few at a time, using models of human skin to probe which vaccine mutations are important in blocking VZV growth in skin.  If we know the cause of attenuation, we could easily improve and make a safer vaccine than the current vaccine virus, and stop the occasional problems some have with current VZV vaccine.

Academic Affiliation

  • 1986-1990 Research Instructor, Dept. of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, MD 
  • 1991-1996 Assistant Professor, Dept. of Ophthalmology, University of Pittsburgh School of Medicine, and Dept. of Molecular Genetics & Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 
  • 1996-2011 Associate Professor, Depts. of Ophthalmology and of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • 2011- current;  Professor, Depts of Ophthalmology and Molecular Microbiology and Genetics, University of Pittsburgh
  • 2018-current;  The Joseph F. Novak, M.D., Chair in Ophthalmology Research
  • 1991- current; Director, Department of Ophthalmology Molecular Biology and Gene expression/array Module CORE Facility

Education & Training

  • University of Leeds, Leeds, England 1979, Microbiology, B.Sc.(Honors)
  • University of Leeds, Leeds, England 1983, Microbiology, Ph.D.
  • Uniformed Services University of The Health Sciences, Bethesda MD Post docotoral fellowship (1983-1986)

Representative Publications

Selected Representative Publications 2015-current

Sex Differences in the Role of Neurexin 3α in Zoster Associated Pain.  Kramer PR, Umorin M, Hornung R, Benson MD, Kinchington PR. Front Integr Neurosci. 2022 Jul 7;16:915797. doi: 10.3389/fnint.2022.915797. eCollection 2022. PMID: 35875508 Free PMC article. 

Neurexin 3α in the Central Amygdala has a Role in Orofacial Varicella Zoster Pain.  Kramer PR, Umorin M, Hornung R, Kinchington PR. Neuroscience. 2022 Aug 1;496:16-26. doi: 10.1016/j.neuroscience.2022.06.003. Epub 2022 Jun 6. PMID: 35679996 Free PMC article. 

Varicella-Zoster virus ORF9 is an antagonist of the DNA sensor cGAS.  Hertzog J, Zhou W, Fowler G, Rigby RE, Bridgeman A, Blest HT, Cursi C, Chauveau L, Davenne T, Warner BE, Kinchington PR, Kranzusch PJ, Rehwinkel J. EMBO J. 2022 Jul 18;41(14):e109217. doi: 10.15252/embj.2021109217. Epub 2022 Jun 7. PMID: 35670106 Free PMC article. 

Studies of Infection and Experimental Reactivation by Recombinant VZV with Mutations in Virally-Encoded Small Non-Coding RNA.  Bisht P, Das B, Borodianskiy-Shteinberg T, Kinchington PR, Goldstein RS. Viruses. 2022 May 10;14(5):1015. doi: 10.3390/v14051015. PMID: 35632756 Free PMC article. 

Development of Robust Varicella Zoster Virus Luciferase Reporter Viruses for In Vivo Monitoring of Virus Growth and Its Antiviral Inhibition in Culture, Skin, and Humanized Mice. Lloyd MG, Yee MB, Flot JS, Liu D, Geiler BW, Kinchington PR*, Moffat JF*(joint lead Authors). Viruses. 2022 Apr 15;14(4):826. doi: 10.3390/v14040826. PMID: 35458556 Free PMC article. 

Antiviral Targeting of Varicella Zoster Virus Replication and Neuronal Reactivation Using CRISPR/Cas9 Cleavage of the Duplicated Open Reading Frames 62/71. Wu BW, Yee MB, Goldstein RS, Kinchington PR. Viruses. 2022 Feb 12;14(2):378. doi: 10.3390/v14020378. PMID: 35215971 Free PMC article. 

Varicella Zoster Virus Neuronal Latency and Reactivation Modeled in Vitro. Goldstein RS, Kinchington PR. Curr Top Microbiol Immunol. 2023;438:103-134. doi: 10.1007/82_2021_244. PMID: 34904194 Review. 

Varicella Zoster Virus Impairs Expression of the Nonclassical Major Histocompatibility Complex Class I-Related Gene Protein (MR1). Purohit SK, Samer C, McWilliam HEG, Traves R, Steain M, McSharry BP, Kinchington PR, Tscharke DC, Villadangos JA, Rossjohn J, Abendroth A, Slobedman B. J Infect Dis. 2023 Feb 1;227(3):391-401. doi: 10.1093/infdis/jiab526. PMID: 34648018 Free PMC article. 

A Guide to Preclinical Models of Zoster-Associated Pain and Postherpetic Neuralgia.  Warner BE, Goins WF, Kramer PR, Kinchington PR. Curr Top Microbiol Immunol. 2023;438:189-221. doi: 10.1007/82_2021_240. PMID: 34524508 Review. 

Varicella Zoster Virus Early Infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of post herpetic neuralgia. Warner BE, Yee MB,  Zhang M, Hornung RS, Kaufer BB, Visalli RJ, Kramer PR, Goins WF, and Kinchington PR. PLOS Path 2021, in press (July 2021)
 
Production of the Cytokine VEGF-A by CD4+ T and Myeloid Cells Disrupts the Corneal Nerve Landscape and Promotes Herpes Stromal Keratitis. Yun H, Yee MB, Lathrop KL, Kinchington PR, Hendricks RL, St Leger AJ.Immunity. 2020 Nov 17;53(5):1050-1062.e5. doi: 10.1016/j.immuni.2020.10.013.
PMID: 33207210
 
A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus. Lloyd MG, Smith NA, Tighe M, Travis KL, Liu D, Upadhyaya PK, Kinchington PR, Chan GC, Moffat JF.  J Virol. 2020 Oct 27;94(22):e01082-20. doi: 10.1128/JVI.01082-20. Print 2020 Oct 27. PMID: 32878893 Free PMC article.
 
Varicella-Zoster Virus (VZV) Small Noncoding RNAs Antisense to the VZV Latency-Encoded Transcript VLT Enhance Viral Replication. Bisht P, Das B, Kinchington PR, Goldstein RS. J Virol. 2020 Jun 16;94(13):e00123-20. doi: 10.1128/JVI.00123-20. Print 2020 Jun 16. PMID: 32295909 Free PMC article.
 
Herpes Simplex Virus 1-Specific CD8+ T Cell Priming and Latent Ganglionic Retention Are Shaped by Viral Epitope Promoter Kinetics. Treat BR, Bidula SM, St Leger AJ, Hendricks RL, Kinchington PR. J Virol. 2020 Feb 14;94(5):e01193-19. doi: 10.1128/JVI.01193-19. Print 2020 Feb 14. PMID: 31826989 Free PMC article.
 
Modeling Varicella Zoster Virus Persistence and Reactivation - Closer to Resolving a Perplexing Persistent State. Laemmle L, Goldstein RS, Kinchington PR. Front Microbiol. 2019 Jul 24;10:1634. doi: 10.3389/fmicb.2019.01634. eCollection 2019. PMID: 31396173 Free PMC article. Review.
 
Influence of an immunodominant herpes simplex virus type 1 CD8+ T cell epitope on the target hierarchy and function of subdominant CD8+ T cells. Treat BR, Bidula SM, Ramachandran S, St Leger AJ, Hendricks RL, Kinchington PR. PLoS Pathog. 2017 Dec 4;13(12):e1006732. doi: 10.1371/journal.ppat.1006732. eCollection 2017 Dec. PMID: 29206240 Free PMC article.
 
Lateral thalamic control of nociceptive response after whisker pad injection of varicella zoster virus. Kramer PR, Stinson C, Umorin M, Deng M, Rao M, Bellinger LL, Yee MB, Kinchington PR. Neuroscience. 2017 Jul 25;356:207-216. doi: 10.1016/j.neuroscience.2017.05.030. Epub 2017 May 24. PMID: 28549561 Free PMC article.

An in vitro model of latency and reactivation of varicella zoster virus in human stem cell-derived neurons. Markus A, Lebenthal-Loinger I, Yang IH, Kinchington PR, Goldstein RS. PLoS Pathog. 2015 Jun 4;11(6):e1004885. doi: 10.1371/journal.ppat.1004885. eCollection 2015 Jun. PMID: 26042814 Free PMC article.
 
Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin. Guedon JM, Zhang M, Glorioso JC, Goins WF, Kinchington PR. Gene Ther. 2014 Jul;21(7):694-702. doi: 10.1038/gt.2014.43. Epub 2014 May 15. PMID: 24830437 Free PMC article.

Research Interest Summary

Molecular biology of herpes viruses that cause eye disease and loss of vision

Research Interests

Infectious viral Eye Diseases 
Varicella Zoster virus
Latency and reactivation
Modeling VZV disease
VZV pathogenesis
VZV attenuation

Research Grants

 

NIH:- NIAID R01 AI158510, Kinchington (PI)
"VZV vaccine attenuation and the DNA Damage response”  07/01/22-06/30/27
Major goals: (1) to determine if the high frequency and near fixed mutations found in the Varicella Zoster virus ORF62 gene (encoding the key VZV regulatory IE62 protein) of the vaccine strain are responsible to the virus attenuation seen for the vaccine in human skin models. (2) to determine if the same mutations alter the ability of the ORF62 protein to regulate the pro-viral DNA damage response to facilitate infection in skin, and if this is mediated through the human differentiating skin specific factor cytokeratin15; (3) To determine if these and other vaccine specific mutations in the IE62 regulatory protein underlie to poor reactivation of VZV from latency, using model reactivatable latent states with cultured neuron platforms.

NIH:- NIAID R01 AI151290, Kinchington (co-PI with Verjans G)
" Role of VZV latency transcript (VLT) and ORF63 in latency and reactivation” 11-15-2020 to 10-30-2025.
The work in this research seeks to characterize the role and expression of the RNAs made from the “VLT” locus that is antisense to ORF61, that is transcribed during VZV latency in human ganglia. Aim 1 seeks to identify neuronal subtypes that host a VZV latent state in which the VLT transcript is expressed. Aim 2 seeks to genetically dissect the VLT locus through the development and evaluation of VZV recombinants. Aim 3 seeks to address the chromatin changes that occur around the VLT locus as the latent state transitions to reactivation.

NIH:- NIAID  1 R21 AI156527-01 Kinchington (PI)
“Small non-coding RNAs of VZV: role in lytic and latent infection” 11-15-2020 to 10-30-2022 
Specific aim 1 seeks to identify the roles of the four small non coding RNAs that are antisense to the VLT transcript and in they regulate VLT expression in lytic infections of epithelial and non-neuronal cells. Specific Aim 2 seeks to determine if the sncRNAs have a role in latency or reactivation using cultured neuron platforms.

NEI P30 EY08098 04/01/04-03/31/24) 
"Core Grant For Vision Research"   
The Core Grant provides support for the five centralized research modules including Histology/Tissue Culture, Molecular Biology and Gene array, Flow Cytometry, Fabrication, and Image acquisition and analyses. Dr Kinchington is Director of the Molecular Biology and Gene array Module

T32 EY 017217 Interdiciplinary Visual Science (IVS) Training Program.  I am contact PI and Codirector with Marlene Behrmann, and we are supported to establish a training program to train the next generation of Vision Scientists at our new Vision Institute at Mercy Pavillion.