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Development of HSV-1 lacking the immunodominant gB498-505 epitope and analyses of the alternative CD8+ T cell response in the murine ocular infection model

Bidula, Sarah (2012) Development of HSV-1 lacking the immunodominant gB498-505 epitope and analyses of the alternative CD8+ T cell response in the murine ocular infection model. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Herpes simplex virus type 1 (HSV-1) establishes latent infections in sensory ganglia such as the trigeminal ganglia (TG), and periodically reactivates to cause repeated corneal infections. These may trigger an immune-mediated corneal disease known as herpes stromal keratitis (HSK), which results in corneal scarring, and eventually blindness. HSK is the most common infectious cause of blindness in the US, affecting over a quarter of a million people annually. Herpes simplex virus type 1 (HSV-1) latent infections in trigeminal ganglia (TG) are associated with persistent CD8+ T cell infiltrate. The ability of such CD8+ T cells to block HSV-1 reactivation from ex vivo ganglionic cultures establish the potential to control reactivation in vivo. As such, targets of CD8+ T cells in the TG will guide vaccination strategies aimed to block reactivation. In latently infected C57BL/6 mice, ~50% of the CD8+ T cell infiltrate in the TG is directed to an immunodominant epitope (residues 498-505) on viral glycoprotein B (gB-CD8). gB-CD8 can block reactivation from latency. Remaining CD8+ T cells in the TG are virus specific, can block reactivation, but are directed to unknown antigens. Given that CD8+ T cells contribute to maintenance of the HSV-1 latent state, it is important to understand viral antigens targeted by these cells and factors influencing dominance hierarchy. Here, we assessed the CD8+ T cell target specificity in TG of C57BL/6 mice infected with HSV-1 lacking and ectopically restored for the gB498-505 epitope. Epitope mutants with near wild type pathogenicity were isolated, and found to induce TG associated CD8+ T cell infiltrates of size similar to that induced by wild type HSV-1, but with little gB498-505-specificity. The nature of the compensated response reflected increase of CD8+ T cell populations directed to most known subdominant epitopes seen in wild type HSV-1 infection. However, a gB498-505 dominated CD8+ T cell response developed following infection with HSV with gB498-505 epitope-mutation that expressed short gB494-509 peptides at an ectopic (gC) locus. We conclude that loss of the HSV dominant epitope does not alter the size of the HSV-specific CD8+ T cell response nor broaden the TCR repertoire, but rather results in a broader dominance hierarchy of subdominant epitopes rising to co-dominance. We further conclude that immunodominance is not a result of properties of the HSV-1 gB protein itself or its genomic locus.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bidula, Sarahsmb154@pitt.eduSMB154
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKinchington, Paulkinchingtonp@upmc.eduKINCH
Committee MemberJenkins, Frankfjenkins@pitt.eduFJENKINS
Committee MemberSalter, Russellrds@pitt.edu RDS
Committee MemberHendricks, Roberthendricksrr@msx.upmc.edu
Date: 5 September 2012
Date Type: Publication
Defense Date: 29 August 2012
Approval Date: 5 September 2012
Submission Date: 4 September 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 97
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Herpes Simplex Virus, immunodominance, subdominance, glycoprotein B
Date Deposited: 05 Sep 2012 12:02
Last Modified: 19 Dec 2016 14:39
URI: http://d-scholarship.pitt.edu/id/eprint/13923

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