Tissue-resident T cell–derived cytokines eliminate herpes simplex virus-2–infected cells
Pavitra Roychoudhury, … , Martin Prlic, Joshua T. Schiffer
Pavitra Roychoudhury, … , Martin Prlic, Joshua T. Schiffer
Published March 3, 2020
Citation Information: J Clin Invest. 2020;130(6):2903-2919. https://doi.org/10.1172/JCI132583.
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Research Article Immunology Virology

Tissue-resident T cell–derived cytokines eliminate herpes simplex virus-2–infected cells

Abstract

The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low CD8+ and CD4+ tissue-resident T cell (Trm cell) density are unknown. We analyzed shedding episodes during chronic HSV-2 infection; viral clearance always predominated within 24 hours of detection even when viral load exceeded 1 × 107 HSV DNA copies, and surges in granzyme B and IFN-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of Trm cells in in situ proliferation, trafficking, cytolytic effects, and cytokine alarm signaling from murine studies with viral kinetics, histopathology, and lesion size data from humans. A sufficiently high density of HSV-2–specific Trm cells predicted rapid elimination of infected cells, but our data suggest that such Trm cell densities are relatively uncommon in infected tissues. At lower, more commonly observed Trm cell densities, Trm cells must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.

Authors

Pavitra Roychoudhury, David A. Swan, Elizabeth Duke, Lawrence Corey, Jia Zhu, Veronica Davé, Laura Richert Spuhler, Jennifer M. Lund, Martin Prlic, Joshua T. Schiffer

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Figure 1

Early and intense immunological pressure against HSV-2 replication within genital microenvironments.

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Early and intense immunological pressure against HSV-2 replication withi...
(A) Three HSV-2 shedding episodes with typical characteristics, including rapid time to first peak viral load and rapid viral clearance. Red circles indicate symptomatic time points. (B–D) Analysis of 83 shedding episodes derived from every 6-hour genital sampling. Box plots with IQR (box) and 1.5 × IQR (whiskers). Categorization according to duration: short, under 24 hours (n = 51); medium, 24 to 48 hours (n = 13); and long, over 48 hours (n = 19). (B) Variable first peak viral loads and (C) durations across episodes, with most episodes eliminated in fewer than 48 hours. (D) Uniform occurrence of first peak viral load within the first 20 hours of HSV-2 detection. (E) Correlation of time to first peak viral load with peak episode viral load (Spearman’s = 0.434, P < 0.001). (F) Correlation of time to first peak viral load with episode duration (Spearman’s = 0.534, P < 0.001). (B–F) Red dots indicate symptomatic episodes, which tend to be longer and associated with higher first peak viral loads.