Year: 2020
Type: article
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.
DOI: 10.1172/jci132583
Institutions: Fred Hutch Cancer Center, University of Washington
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Harnessing Tissue Resident Memory T Cells for Immunotherapy of Herpes Virus Infections, Identification of Novel Mucosal Immune Mechanisms Involved in Protection from HIV-1, G2842608439, Clinical Epidemiology and Pathogenesis of Asymptomatic HSV, Mechanisms of Protective Local Immunity in Human Female Reproductive Tract, G37498967, Diseases of Public Health Importance Training Grant, Modeling of human HSV infection: development of immune-competent 3D skin-on-chip with vascular perfusion, University of Washington/Fred Hutch Center for AIDS Research, Institutional Career Development Core
OpenAlex ID: W3012094413