In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation.
Herpes simplex virus type 2 (HSV-2) reactivation is accompanied by a sustained influx of CD4(+) and CD8(+) T cells that persist in genital tissue for extended periods. While CD4(+) T cells have long been recognized as being present in herpetic ulcerations, their role in subclinical reactivation and persistence is less well known, especially the role of CD4(+) regulatory T cells (Tregs).



We characterized the Treg (CD4(+)Foxp3(+)) population during human HSV-2 reactivation in situ in sequential genital skin biopsy specimens obtained from HSV-2-seropositive subjects at the time of lesion onset up to 8 weeks after healing.



High numbers of Tregs infiltrated to the site of viral reactivation and persisted in proximity to conventional CD4(+) T cells (Tconvs) and CD8(+) T cells. Treg density peaked during the lesion stage of the reactivation. The number of Tregs from all time points (lesion, healed, 2 weeks after healing, 4 weeks after healing, and 8 weeks after healing) was significantly higher than in control biopsy specimens from unaffected skin. There was a direct correlation between HSV-2 titer and Treg density.



The association of a high Treg to Tconv ratio with high viral shedding suggests that the balance between regulatory and effector T cells influences human HSV-2 disease.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center.
Neta
N
Milman
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine.
Jia
J
Zhu
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Medicine.
Christine
C
Johnston
Department of Biostatistics.
Anqi
A
Cheng
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine Department of Medicine Department of Biostatistics.
Amalia
A
Magaret
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine Department of Medicine Department of Global Health, University of Washington, Seattle.
David M
DM
Koelle
Department of Laboratory Medicine.
Meei-Li
ML
Huang
Department of Laboratory Medicine.
Lei
L
Jin
Department of Laboratory Medicine.
Alexis
A
Klock
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center.
Erik D
ED
Layton
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Laboratory Medicine Department of Medicine.
Lawrence
L
Corey
D005260:Female; D005835:Genitalia / Q000294:innervation* / Q000821:virology*; D006558:Herpes Genitalis / Q000503:physiopathology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000821:virology*; D014775:Virus Activation / Q000502:physiology*; D017201:Virus Shedding / Q000502:physiology*; D014861:Washington
Foxp3; HSV-2; T cells; herpes; reactivation; regulatory T cells; viral shedding