title: Virologic and immunologic evidence of multifocal genital herpes simplex virus 2 infection.
abstract: Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4(+) and CD8(+) T cells were quantified by immunofluorescence, and HSV-specific CD4(+) T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8(+) T cells compared to control tissue (27 versus 13 cells/mm(2), P = 0.03) and identified HSV-specific CD4(+) T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract.
  
  
  OBJECTIVE
  This detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8(+) T cells compared to control tissue, and HSV-specific CD4(+) T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Johnston
authors.forename: Jia
authors.initials: J
authors.lastname: Zhu
authors.forename: Lichen
authors.initials: L
authors.lastname: Jing
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Laing
authors.forename: Christopher M
authors.initials: CM
authors.lastname: McClurkan
authors.forename: Alexis
authors.initials: A
authors.lastname: Klock
authors.forename: Kurt
authors.initials: K
authors.lastname: Diem
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Stanaway
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tronstein
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Meei-Li
authors.initials: ML
authors.lastname: Huang
authors.forename: Stacy
authors.initials: S
authors.lastname: Selke
authors.forename: Youyi
authors.initials: Y
authors.lastname: Fong
authors.forename: Amalia
authors.initials: A
authors.lastname: Magaret
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
authors.forename: Anna
authors.initials: A
authors.lastname: Wald
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006558:Herpes Genitalis / Q000473:pathology*; D018258:Herpesvirus 2, Human / Q000302:isolation & purification* / Q000502:physiology*; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D014775:Virus Activation; D017201:Virus Shedding; D055815:Young Adult
chemical_list: D016207:Cytokines; D004279:DNA, Viral