A Conversation With Dr. Kinchington
Kip Kinchington, PhD. I have long been interested in the viruses that potentially cause blinding infections of the eye. I have been a part of the Department of Ophthalmology at Pitt since 1991, working on the human herpesviruses that cause vision loss. I am particularly interested in how they switch between active growth for production of virus;, and a dormant “latent” state, in which the virus remains quiet in the neurons of the host for life. The sporadic reawakening of latent virus inflicts repeated damage on tissues:- when this occurs in the eye, it can devastate vision by clouding the cornea or even destroying the retina. There two herpesviruses that do this are herpes simplex virus type 1 (which commonly causes cold sores): and Varicella zoster virus (VZV) the cause of chickenpox and the much more debilitating elderly disease, Herpes Zoster (or Shingles). Zoster in the eye can be blinding, painful and have long term effects, leaving the cornea completely lacking any sensation. This opens the eye up to infections and iatrogenic damage. As a molecular virologist, I felt the opportunity was ripe to combine molecular virology with ophthalmology to study how these viruses cause visual diseases.
Pitt also offered a huge and exciting opportunity to collaborate. I went on to direct a Molecular Biology core module of the NEI funded CORE grant EY08098 , something I have done now for more than 30 years. Its mission is to provide molecular biology expertise to others who do not have the skills or knowhow to manipulate DNA, quantify nucleic acids and express genes in vectors or cells of their choice. By directing the module, I was able to help many NEI-funded researchers and Investigators. My own research programs use all these methods and skills. The unit is kept up-to date in the ever-evolving methods, kits and techniques, so that they can be applied to many vision research programs at Pitt.
My current research focuses on VZV, which is not easy to work with: I am one of a few with the expertise to grow and manipulate it. I seek to understand how it causes pain, eye diseases and the problems associated with Shingles. There are three VZV projects. The first seeks to understand why Shingles is so painful. For many Shingles acute pain can turn into severe debilitating long term pain called post herpetic neuralgia, or PHN. We have developed an exciting new facial model that mimics the pain seen in facial shingles and are using it and a footpad model to evaluate new pain-relieving treatments. The second project is to understand how the virus infects neurons and nerve cells to stay quiet, and then what the triggers are to cause it to re-awaken to cause Shingles. We developed a new cultured human neuron platform to examine how virus spreads between neurons (which it does in shingles) and moves up and down neurons to get from the eye to the nerve cell bodies in the ganglia. We are testing ways to remove the latent virus from neurons using CRSPR-cas9 systems. The final VZV project is seeking to understand why the live virus used in the VZV vaccines are attenuated for growth in human skin. We have several models of human skin and are probing the specific vaccine mutations that reduce skin growth. If we know the cause of attenuation, we could improve the vaccines so they do not have the occasional problems associated with current vaccination.
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)
Selected Representative Publications 2015-current
- Stem cell transplantation rescued a primary open-angle glaucoma mouse model.
Xiong S, Kumar A, Tian S, Taher EE, Yang E, Kinchington PR, Xia X, Du Y.
Elife. 2021 Jan 28;10:e63677. doi: 10.7554/eLife.63677.
PMID: 33506763 Free PMC article.
- 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.
- 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.
- Reduced activity of GAD67 expressing cells in the reticular thalamus enhance thalamic excitatory activity and varicella zoster virus associated pain.
Hornung R, Pritchard A, Kinchington PR, Kramer PR. Neurosci Lett. 2020 Sep 25;736:135287. doi: 10.1016/j.neulet.2020.135287. Epub 2020 Aug 4. PMID: 32763361
- 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.
- Varicella-Zoster Virus Expresses Multiple Small Noncoding RNAs.
Markus A, Golani L, Ojha NK, Borodiansky-Shteinberg T, Kinchington PR, Goldstein RS.
J Virol. 2017 Nov 30;91(24):e01710-17. doi: 10.1128/JVI.01710-17. Print 2017 Dec 15.
PMID: 29021397 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.
- Neuronal changes induced by Varicella Zoster Virus in a rat model of postherpetic neuralgia.
Guedon JM, Yee MB, Zhang M, Harvey SA, Goins WF, Kinchington PR.
Virology. 2015 Aug;482:167-80. doi: 10.1016/j.virol.2015.03.046. Epub 2015 Apr 11.
PMID: 25880108 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.
Erazo A, Kinchington PR. Varicella-Zoster Virus Open Reading Frame 66 Protein Kinase and Its Relationship to Alphaherpesvirus US3 Kinases. Curr Top Microbiol Immunol. 2010 342, 79-98 PMID: 20186610
Kinchington PR and A Abendroth. Immunity and immune evasion in varicella zoster virus. In “The alphaherpesviruses” 2nd Edition, Ed by S Weller (Published Mar 2011) Caister Academic Press
Abendroth A, P. R. Kinchington and B Slobedan. Immune evasion strategies employed by varicella zoster virus. Current Topics in Microbiology and Immunology 2010 342, 155-172 PMID: 20563710
Kinchington PR. CNS infections by Varicella Zoster Virus- Chapter in “Virus in CNS disease”
Ed By S. Singh, Taylor Publishing
Infectious Eye Diseases: Zoster Laboratory WWI 1020
NIH:- NIAID R01 AI151290, Kinchington (co-PI with Verjans G and Cohrs R)
" 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.
NIH:- NINDS R01 NS064022, Kinchington (PI)
"A rat model for Varicella Zoster Virus induced post herpetic neuralgia” 1-15-2009 to 5-30-2021. The work in this program aims to identify the mechanisms underlying the ability of VZV to induce long term behavioral responses indicative of pain. The project also aims to develop VZV mutants that lack the ability to induce pain and uses novel viral delivery strategies to suppress the pain induced by VZV.
NIH:- NIAID R01 AI122640 Kinchington (PI)
A New in vitro model of axonal transport and latency of VZV. 11-01-2015-010-30-2021 The Project uses peripheral neurons developed from human embryonic stem cells, induced pluripotent stem cells and neural progenitor lines in conjunction with fluorescent reporter VZV to track virus nuclecapsid transport in axons as well as monitor latency and persistence.
NEI P30 EY08098 04/01/04-03/31/24)
"Core Grant For Vision Research" The Core Grant will provide 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 o9f the Molecular Biology and Gene array Module