Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract

6 figures, 9 videos and 6 tables

Figures

Figure 1 with 3 supplements
HSV-2 levels in the genital tract are stable over minutes, expand and decay markedly over hours, and fluctuate rapidly and unpredictably over days.

(A) Shedding quantity in a participant, who performed genital swabs every 5 min over 4 hr during a lesion, reveals low swab-to-swab variation in viral quantity. Using data from panel (A and B), absolute mean difference (R2 = 0.99), and (C) mean difference (R2 = 0.87), in HSV DNA copies between swabs, are a function of time between swabs. (D) Shedding quantity in a participant, who performed 10 genital swabs per day during a lesion over 4 days (swabs every 2–4 hr), shows a characteristic saw-tooth pattern; arrows denote rapid viral re-expansion; the participant had a negative swab performed before episode onset. (E) Shedding quantity in a participant, who performed four genital swabs per day over 17 days demonstrates that rapid and frequent viral re-expansion allows for shedding prolongation; four missing data points are left blank.

https://doi.org/10.7554/eLife.00288.007
Figure 1—source data 1

Source data for Figure 1, Figure 1—figure supplement 1, Figure 1—figure supplement 2 and Figure 1—figure supplement 3.

https://doi.org/10.7554/eLife.00288.008
Figure 1—figure supplement 1
Dynamics of HSV-2 shedding over 5-min time intervals.

(A) and (B) Shedding quantity in two participants, who performed genital swabs every 5 min over 4 hr during a lesion, reveals low swab-to-swab variation in viral quantity. (C) Using data from panels (A and B), absolute mean difference in HSV DNA copies between swabs, correlated moderately with time between swabs in one participant (green line R2 = 0.60) due to steady viral decay, but was more stable as a function of time in the other participant due to peaking overall viral load (blue line, R2 = 0.16). (D) Using data from panels (A and B), mean difference in HSV DNA copies between swabs, was a function of time between swabs in the participants (green line R2 = 0.89, and blue line R2 = 0.85) presumably because viral load was generally decaying during most of the 4-hr window (green) or gradually expanding during most of the 4-hr window (blue).

https://doi.org/10.7554/eLife.00288.009
Figure 1—figure supplement 2
Dynamics of HSV-2 shedding with every 2-4 hr sampling.

Shedding quantity in four participants, who performed 10 genital swabs per day over 4–5 days during a lesion reveal a characteristic saw-tooth pattern; arrows denote re-expansion. Participants had swabbing initiated upon visualization of lesions. The participant in panel d initiated swabbing ∼16 hr after lesion detection.

https://doi.org/10.7554/eLife.00288.010
Figure 1—figure supplement 3
Dynamics of HSV-2 shedding with every 6-hr sampling over 8 days.

Shedding quantity in episodes detected in a participant who performed four genital swabs per day over 60 days demonstrates that viral re-expansion allows for shedding prolongation.

https://doi.org/10.7554/eLife.00288.011
Figure 2 with 3 supplements
HSV-2 replicates and is contained in widely dispersed microenvironments across the genital tract.

(A) HSV shedding quantity in a participant, who underwent daily swabs in 23 regions across the genital tract for 30 days; days without sampling are marked with an X; stars denote days with a lesion; virus is widely dispersed and several prolonged episodes with heterogeneous viral loads across the genital tract are noted. (B) Increasing probability of episode re-expansion (nonmonotonic episodes) as a function of peak episode copy number among 1020 episodes from 531 study subjects; individual peaks during episodes may represent virus from a single ulcer that can seed other regions. (C) A genital lesion consists of numerous round ulcers (black dotted circle) clustered in space; contemporaneous presence of multiple ulcers may indicate concurrent viral expansion in decay in multiple regions. (D) and (E) Immunofluorescent staining of biopsies performed (D) at the edge, and (E) 1 cm away from an ulcer 3 days post-healing; CD8+ T cells (green) at the dermal–epidermal junction (arrow) are highly localized to ulcer edge (287/mm2) and are fourfold less dense 1 cm away (72/mm2).

https://doi.org/10.7554/eLife.00288.013
Figure 2—source data 1

Source data for Figure 2 and Figure 2—figure supplement 1.

https://doi.org/10.7554/eLife.00288.014
Figure 2—figure supplement 1
Spatial features of HSV genital tract shedding.

HSV shedding quantity in a study participant, who underwent daily swabs in 23 regions across the genital tract for 30 days; days without sampling are marked with an X. The participant had three brief localized episodes with low viral copy number in three separate localized regions.

https://doi.org/10.7554/eLife.00288.015
Figure 2—figure supplement 2
Spatial features of HSV-2 lesions.

A genital lesion consists of numerous round ulcers or vesicles (black dotted circle), clustered in space.

https://doi.org/10.7554/eLife.00288.016
Figure 2—figure supplement 3
Spatial features of CD8+ T-cell response in genital skin.

Immunofluorescent staining of a biopsy performed (A) at the edge, and (B) 1 cm away from an ulcer 3 days post-healing. CD8+ T-cells (red) and CD4+ T-cells (green) at the dermal epidermal junction (arrow) are highly localized to ulcer edge (132/mm2 and 447/mm2, respectively), and are less dense 1 cm away (91/mm2 and 132/mm2, respectively).

https://doi.org/10.7554/eLife.00288.017
Figure 3 with 1 supplement
Mathematical model.

(A) Microregions are linked virally because cell-free HSV-2 can seed surrounding regions, and immunologically based on overlapping CD8+ T-cell densities between regions (not shown). (B) Schematic for HSV-2 infection within a single genital tract microenvironment. Equations capture seeding of epithelial cells by neuronal HSV-2, replication of HSV-2 within epithelial cells, viral spread to other epithelial cells, cytolytic CD8+ T-cell response to infected cells, transition of cell-associated HSV-2 to cell-free HSV-2 following lysis of infected cells, and elimination of free virus and infected cells.

https://doi.org/10.7554/eLife.00288.019
Figure 3—figure supplement 1
Spatial mathematical model.

Viruses produced from neurons (green), cell-associated viruses from epidermal cells (yellow), and cell-free viruses (orange) that form after rupture of epidermal cells, are distinguished in the model. Neuron-derived viruses are released throughout the genital tract and are responsible for ulcer initiation within specific regions (grey hexagons). Cell-associated HSV particles contribute to ulcer expansion (white circle) within a region. Cell-free particles initiate secondary ulcers in adjacent regions (upper right) leading to concurrent ulcers where HSV production occurs. Cytolytic CD8+ T-cell (purple circles) response is localized within each region. Regions have a maximum diameter of 6.5 mm. However, distance between regions is considered in terms of immunologic co-dependence rather than a physical distance. Seven of 300 total model regions are illustrated.

https://doi.org/10.7554/eLife.00288.020
Figure 4 with 1 supplement
The spatial model reproduces all shedding episode characteristics.

Colored bars represent results from (A) 14,685 genital swabs and (BG) 1020 shedding episodes from 531 study participants. The model simulation, represented with black bars in each panel, continued until 1020 episodes were generated; model sampling occurred every 24 hr as in the clinical protocol. Model output reproduced (A) quantitative shedding frequency as well as (B) rate, (C) median initiation to peak and peak to termination slopes, (D) Duration, (E) first HSV DNA copy number, (F) last HSV DNA copy number, and (G) peak HSV DNA copy number of episodes.

https://doi.org/10.7554/eLife.00288.021
Figure 4—figure supplement 1
Continuous sampling of spatial model output reveals more accurate measures of episode characteristics.

We subjected a 30-year simulation to daily and continuous sampling. (A) Median initiation to peak slope, and (B) peak to termination slopes increased substantially with continual sampling. (C) Shedding frequency was similar regardless of sampling frequency. (D) Continuous sampling detected 842 episodes (28.1/year) vs 450 episodes (15.0/year) with daily sampling. The 392 additional episodes were all less than a day in duration and mostly <104 peak HSV DNA copies per milliliter, skewing the distributions of (E) episode duration and (F) peak HSV DNA copy number. (G) Total number of episodes at low and high-peak copy numbers increased with continual sampling.

https://doi.org/10.7554/eLife.00288.023
Containment of infected cells within a single ulcer is extremely rapid, although secondary ulcers explain prolonged episodes.

(A) Episode duration was a function of the number of ulcers before episode termination during 500 simulated episodes. (B)–(E) A 10-day simulated episode consisting of 24 ulcers: (B) Total cell-free virus (red) over time reflects the saw-tooth pattern of prolonged episodes; virus produced from the initial ulcer (red dotted line) was eliminated within 3 days. (C) Infected cells were eliminated from the initial viral ulcer (green dotted line) within 1 day and there were four periods during the episode when no infected cells were present. (D) Cell-free virus (red), cell-associated virus (blue), and infected cells (green) were eliminated from the primary ulcer with different kinetics; infected cells peaked at 13 hr and were extinguished in <24 hr (E) Secondary ulcers prolonged episodes; each thin line represents HSV-2 production from a specific region.

https://doi.org/10.7554/eLife.00288.026
Figure 6 with 2 supplements
Random spatial dispersion of viral particles from neurons reproduced the full diversity of episode characteristics if particles were released continuously, daily, or weekly from neurons.

White circles represent results from (A) 14,685 genital swabs and (BG) 1020 shedding episodes from 531 study participants (Figure 4). The model simulations represented with colored bars in each panel continued until 1020 episodes were generated. Sampling occurred every 24 hr as in the clinical protocols. Model output with release of virus randomly throughout the 300 regions on a continuous (pink), daily (purple), every 3 days (blue), and weekly (orange) basis at an average rate of 82 HSV DNA particles per day reproduced (A) quantitative shedding frequency and episode, (B) rate, (C) median initiation to peak slope and peak to termination slopes, (D) Duration, (E) first HSV DNA copy number, (F) last HSV DNA copy number, and (G) peak HSV DNA copy number.

https://doi.org/10.7554/eLife.00288.036
Figure 6—figure supplement 1
Random spatial dispersion of viral particles from neurons reproduced the full diversity of episode characteristics during simulations in which particles were released into only a minority of the 300 modeled regions.

White circles represent results from (A) 14,685 genital swabs and (BG) 1020 shedding episodes from 531 study participants (Figure 4). The model simulations represented with colored bars in each panel continued until 1020 episodes were generated. Sampling occurred every 24 hr as in the clinical protocols. Model output with continuous release (82 HSV DNA particles per day) of virus randomly to 300 (pink), 100 (blue), and 50 (brown) regions reproduced (A) quantitative shedding frequency and episode, (B) rate, (C) median initiation to peak slope and peak to termination slopes, (D) Duration, (E) first HSV DNA copy number, (F) last HSV DNA copy number, and (G) peak HSV DNA copy number. Model output with continuous release (82 HSV DNA particles per day) of virus randomly to 20 (yellow), 5 (light blue), and 1 (red) region underestimated (A) quantitative shedding frequency and episode, (B) rate, (D) Duration, (E) first HSV DNA copy number, and (G) peak HSV DNA copy number.

https://doi.org/10.7554/eLife.00288.037
Figure 6—figure supplement 2
Dispersion of viral particles from neurons reproduced the full diversity of episode characteristics during simulations in which particles were released into a minority of modeled regions, provided that dispersion was random rather than clustered within a single geographic region.

White circles represent results from (A) 14,685 genital swabs and (BG) 1020 shedding episodes from 531 study participants (Figure 4). The model simulations represented with colored bars in each panel continued until 1020 episodes were generated. Sampling occurred every 24 hr as in the clinical protocols. Model output with continuous release (82 HSV DNA particles per day) of virus to 50 randomly dispersed regions (brown) reproduced (A) quantitative shedding frequency and episode, (B) rate, (C) median initiation to peak slope and peak to termination slopes, (D) Duration, (E) first HSV DNA copy number, (F) last HSV DNA copy number, and (G) peak HSV DNA copy number. Model output with continuous release (82 HSV DNA particles per day) of virus to 50 clustered regions (green) underestimated (A) shedding frequency due only to (B) too low of an episode rate with daily sampling.

https://doi.org/10.7554/eLife.00288.038

Videos

Video 1
Spatiotemporal demonstration of a 10-day episode.

The left panel represents total cell-free HSV DNA copies per milliliter present over time. The right panel represents spatial spread of virus during the episode, each hexagon contains one region of shedding and virus spreads to contiguous regions. Amount of virus within a single region is displayed according to a heat map adjacent to the spatial map.

https://doi.org/10.7554/eLife.00288.025
Video 2
Spatiotemporal demonstration of a 14-day episode according to viral production within each single region.

The left panel represents cell-free HSV DNA measured over time with each region's production demonstrated with a different color. The right panel represents spatial spread of virus during the episode; colors in the right panel correspond to those in the left panel. Amount of virus within a region is displayed according to a heat map adjacent to the spatial map.

https://doi.org/10.7554/eLife.00288.027
Video 3
Spatiotemporal demonstration of infected cell and viral spread during a 6-day episode.

The upper left panel represents spatial spread of cell-free virus during the episode; the upper right panel represents spatial spread of cell-associated virus during the episode; the bottom left panel represents spatial spread of infected cells during the episode; the bottom right panel represents ulcer formation during the episode, ulcers turn from black to red when diameter exceeds 1 mm; quantities are displayed according to a heat map adjacent to each spatial map. There is more rapid decay of infected cells and cell-associated particles than of cell-free particles within each region. Visible ulcers persist after viral production terminates within a region.

https://doi.org/10.7554/eLife.00288.028
Video 4
Spatiotemporal demonstration of 365 days of simulated shedding.

The left panel represents total cell-free HSV DNA copies per milliliter present over time. The right panel represents spatial spread of virus during the episode; each hexagon contains one region of shedding and virus spreads to contiguous regions. Amount of virus within a single region is displayed according to a heat map adjacent to the spatial map. The simulation is notable for episodes of variable duration and peak HSV DNA copy number. Prolonged episodes at days 8, 38, 136, 158, and 288, display several re-expansion phases.

https://doi.org/10.7554/eLife.00288.029
Video 5
Spatiotemporal demonstration of 365 days of simulated shedding with noninfectious cell-free particles.

The left panel represents total cell-free HSV DNA copies per milliliter present over time. The right panel represents spatial spread of virus during the episode; each hexagon contains one region of shedding. Amount of virus within a single region is displayed according to a heat map adjacent to the spatial map. The simulation is notable for lack of prolonged episodes and lack of episode re-expansion.

https://doi.org/10.7554/eLife.00288.030
Video 6
Spatiotemporal demonstration of immune response to a pair of 2-day episodes.

The upper left panel represents total cell-free HSV DNA copies per milliliter present over time. The upper right panel represents spatial spread of cell-free virus during the episode. The lower left panel represents CD8+ T-cell density within each region. The lower right panel indicates reproductive number within each region. Quantities are displayed according to a heat map adjacent to each spatial map. Areas with high CD8+ T-cell levels and low reproductive numbers do not support high-level viral production. The simulated episodes are short because virus does not spread from the initial plaque to adjacent regions with high CD8+ T-cell density and reproductive numbers less than one.

https://doi.org/10.7554/eLife.00288.032
Video 7
Spatiotemporal demonstration of immune response to a 7-day episode.

The upper left panel represents total cell-free HSV DNA copies per milliliter present over time. The upper right panel represents spatial spread of cell-free virus during the episode. The lower left panel represents CD8+ T-cell density within each region. The lower right panel indicates reproductive number within each region. Quantities are displayed according to a heat map adjacent to each spatial map. The simulated episode is medium length because virus spreads from the initial region to adjacent regions with low CD8+ T-cell density and reproductive numbers less than one, but is ultimately contained when it reaches an anatomic edge region outside of the genital tract, and regions of high CD8+ T-cell density and low reproductive number within the genital tract.

https://doi.org/10.7554/eLife.00288.033
Video 8
Spatiotemporal demonstration of immune response to a 14-day episode.

The upper left panel represents total cell-free HSV DNA copies per milliliter present over time. The upper right panel represents spatial spread of cell-free virus during the episode. The lower left panel represents CD8+ T-cell density within each region. The lower right panel indicates reproductive number within each region. Quantities are displayed according to a heat map adjacent to each spatial map. The simulated episode is prolonged because virus spreads from the initial region to adjacent regions with low CD8+ T-cell density and reproductive numbers less than one, and is not contained until many regions of the genital tract are infected.

https://doi.org/10.7554/eLife.00288.034
Video 9
Spatiotemporal demonstration of immune response over 20 years.

The left panel represents CD8+ T-cell density within each region. The right panel indicates reproductive number within each region. Quantities are displayed according to a heat map adjacent to each spatial map. CD8+ T-cells expand rapidly at sites of episodes and then decay slowly over time, correlating with decreases and increases in reproductive number respectively. CD8+ T-cell and reproductive number spatial patterns cycle intermittently between a patchwork of heterogeneous density, broad low density, broad high density, and stark division between regions of high and low density. However, CD8+ T-cell density is virtually always high in at least some regions of the genital tract.

https://doi.org/10.7554/eLife.00288.035

Tables

Table 1

Five cohorts of HSV-2 genital tract shedding

https://doi.org/10.7554/eLife.00288.003
CohortSubjectsTotal swabsSwabbing frequencyTotal episodesSwabbing durationAnatomic swabbing regionPurpose
A396Every 5 min34 hr when lesion presentTotal genital tractSwab-to-swab sampling/assay variability
B520010 times/day (every 2 hr during the days and 4 hr overnight)54–5 days when lesion presentTotal genital tractEpisode expansion, clearance and re-expansion kinetics
C2547064 times/day10930–60 days without or with a lesionTotal genital tractAccurate estimates for expansion/decay slopes for clinical and subclinical episodes
D2216Daily430 days without or with a lesion23 separate regionsSpatial dispersion of HSV
E53114,685Daily1020>30 days with or without a lesionTotal genital tractModel fit
Table 2

Parameter ranges that result in accurate reproduction of model outcomes

https://doi.org/10.7554/eLife.00288.024
ParameterUnitsSymbolBest fit valueGood fitAverage fit
Lower limitUpper limitLower limitUpper limit
Cell-associated HSV infectivityDNA copy days/cell (viruses needed per day to infect one adjacent cell)βi5.4e−8 (111)4.86e−8 (123)7.83e−8 (76)3.78e−8 (158)1.32e−7 (45)
Cell-free HSV infectivityDNA copy days/cell (viruses needed per day to initiate one new ulcer)βe2.65e−11 (2.26e5)1.73e−11 (3.46e5)2.78e−11 (2.15e5)3.98e−12 (1.50e6)5.04e−11 (1.19e5)
Epidermal HSV replication rateHSV DNA copies per cell per dayp1.03e57.21e41.7e55.15e41.96e5
Neuronal release rateHSV DNA copies per day per genital tractϕ82459041123
Free-viral decay ratePer day (half-life, hours)c8.8 (1.9)7.0 (2.4)9.7 (1.7)6.2 (2.7)12.3 (1.4)
Maximal CD8+ T-cell expansion ratePer dayθ2.841.853.271.855.25
CD8+ T-cell decay ratePer day (half-life, days)δ1.47e−3 (471)1.12e−3 (619)1.69e−3 (409)6.64e−4 (1040)2.21e−3 (314)
CD8+ T-cell local recognitionInfected cells at which θ is half maximalr423047474
CD8+ regional codependence0 = no codependence, 1 =full codependenceρ0.690.590.860.380.86
Viral production lagDaysε0.960.531.10.341.1
Table 3

Predictive model parameters for key model outcomes

https://doi.org/10.7554/eLife.00288.031
Single episode featuresLong-term shedding features
Peak viral loadDurationShedding rateEpisode rate
CD8+ T-cell density at reactivation site−0.56−0.47NANA
Cell-associated HSV infectivity0.120.13
Cell-free HSV infectivity
Epidermal cell replicate rate0.130.14−0.25−0.31
Neuronal release rate0.430.55
Free-viral decay rate−0.2
Maximal CD8+ T-cell expansion rate−0.090.370.51
CD8+ T-cell decay rate0.09−0.16
CD8+ T-cell local recognition
CD8+ regional co-dependence0.320.34
Viral production lag0.240.23
  1. Partial correlation coefficients are listed only for parameters that are found to improve predictive effect on outcomes using Akaike information criteria models. Episode features are from 500 single episode simulations. Long-term shedding outcomes were measured over 10-years during 500 simulations.

Table 4

Spatial model simulations that varied only according to duration of sampling (30 days, 60 days, 365 days, and 10 years)

https://doi.org/10.7554/eLife.00288.039
Simulation durationPercent of time with HSV DNA > 150 copies per mLPercent of time with lesions* presentEpisodes per yearLesions per year
30 dayMean13.77.6113.2
Median3.40120
Range0–82.80–58.80–36.50–24.3
60 dayMean19.09.813.44.4
Median18.63.4126
Range0–54.20–46.90–42.60–18
365 dayMean19.610.114.34.6
Median19.99.9144
Range7.1–36.82.3–228–241–9
10 yearMean17.59.114.54.3
Median17.69.014.54.2
Range14.8–19.81.9–12.811.5–17.11.4–6
  1. *

    Lesions were defined as > 1 mm diameter ulcers.

  2. Sixty simulations were performed at each of the sampling durations. Within shorter sampling duration simulations, lesion, and shedding frequency varied significantly, while ranges narrowed with prolonged sampling.

Table 5

Mathematical models of HSV-2 pathogenesis

https://doi.org/10.7554/eLife.00288.040
ModelEquations (additions to previous model are denoted in bold)Variables (model fitting variable)New features
1 (Schiffer et al., 2009; Schiffer et al., 2010)ΔS=[λ(βi×S×V)(βi×S×Vneu)]ΔtΔI=[(βi×S×Vi)+(βi×S×Vneu)(a×I)(f×I×E)]ΔtΔE=[(F(I)×θ×E)(δ×E)]ΔtΔVi=[(p×I)(c×Vi)(βi×S×Vi)]ΔtΔVneu=[φ(c×Vneu)(βi×S×Vneu)]ΔtF(I)=I/(I+r)Vtot=Vi+Vneuλ=d(SS0)S, I, E, Vi Vneu,
2ΔS=[λ(βi×S×V)(βi×S×Vneu)]ΔtΔI=[(βi×S×Vi)+(βi×S×Vneu)(a×I)(f×I×E)]ΔtΔE=[(F(I)×θ×E)(δ×E)]ΔtΔVneu=[φ(c×Vneu)(βi×S×Vneu)]ΔtΔVi=[(p×I)(a×Vi)(βi×S×Vi)]ΔtΔVe=[(a×Vi)(c×Ve)]ΔtF(I)=I/(I+r)Vtot=Vi+Ve+Vneuλ=d(SS0)S, I, E, Vi, Vneu, (Ve)Cell-free and cell-associated particles
3ΔS(i300)==[λ(βi×S×Vi)(βi×S×Vneu)(βe×S×Ve)]ΔtΔI(i300)=[βi×S×Vi)+(βi×S×Vneu)(βe×S×Vetot)(a×l)(f×l×E]ΔtΔS(i300)=[(F(I)×θ×E)(δ×E)]ΔtΔVneu(i300)=[φ(c×Vneu)(βi×S×Vneu)]ΔtΔVi(i300)=[(p×I)(a×Vi)(βi×S×Vi)ΔtΔVe(i300) = [(a×Vi)(c×Ve)]ΔtF(I) =I/(I+r)Itot=I1+I2++Ie300Vetot=Ve1+Ve2++Ve300Vitot=Vi1+Vi2++Vi300λ=d(SS0)S, I, E, Vneu, Vitot, (Vetot)Concurrent plaques from cell-free particles
4*S0=1.67 e5 per regionΔS(i300)=[λ(βi×S×Vi)(βi×S×Vneu)(βe×S×Ve)]ΔtΔI(i300)=[(βi×S×Vi)+(βi×S×Vneu)+(βe×S×Veadj)(a×I)(f×I×E)]ΔtΔE(i300)=[(F(I)×θ×E)(δ×E)]ΔtΔVneu(i300)=[φ(c×Vneu)(βi×S×Vneu)]ΔtΔVi(i300)=[(p×I)(a×Vi)(βi×S×Vi)]ΔtΔVe(i300)=[(a×Vi)(c×Ve)]Δtλ=d(SS0)F(I)=I/(I+r)Veadj=Vefrom 6 adjacent regionsItot=I1+I2++I300Vetot=Ve1+Ve2++Ve300Vitot=Vi1+Vi2++Vi300S, I, E, Vneu, Vitot, (Vetot)Spatial model
  1. *Model 4 has a parameter of regional CD8+ co-dependence (ρ) within each plaque-forming region. At episode onset within a region, the CD8+ density is adjusted to infer the spatial co-dependence of CD8 density from surrounding regions: Ei (time + 0.001) = (Ei × (1 − ρ)) + (Eavg × ρ) where Eavg is average of E from the 6 surrounding regions.

  2. Models are described in the ‘Methods’. Units and values of each parameter in the optimized model are listed in Table 2. Variables include: S (susceptible skin cells), I (infected skin cells), E (CD8+ T cells), Vi (cell-associated HSV DNA particles), and Ve (cell-free HSV DNA particles).

Table 6

Model fit to Cohort E

https://doi.org/10.7554/eLife.00288.041
Summary measureSummed criteria scoresBest fitting scoreAIC
Shedding frequencyEpisode durationFirst positive swabLast positive swabPeak positive swabMedian expansionMedian decayEpisode frequency
Model 12.135.590.050.080.240.070.430.018.61−50
Model 21.268.330.380.340.220.040.090.0310.69−41
Model 30.253.750.310.220.610.050.500.225.92−62
Model 4 solved for 10 parameters0.250.130.290.150.090.010.010.030.96−139
Model 4 solved for 5 parameters0.390.320.440.210.090.0400.181.67−125
  1. Summed criteria scores measure the degree of fit for each model according the eight individual shedding episode features using a weighted sum of squares. Model 4 is the spatial model. Models 1–3 are described in the ‘Methods’. Best fitting score is a sum of all summed criteria scores for a particular model with lower scores indicating better fit. AIC: Akaike information criteria with lower scores indicating better fit.

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  1. Joshua T Schiffer
  2. David Swan
  3. Ramzi Al Sallaq
  4. Amalia Magaret
  5. Christine Johnston
  6. Karen E Mark
  7. Stacy Selke
  8. Negusse Ocbamichael
  9. Steve Kuntz
  10. Jia Zhu
  11. Barry Robinson
  12. Meei-Li Huang
  13. Keith R Jerome
  14. Anna Wald
  15. Lawrence Corey
(2013)
Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract
eLife 2:e00288.
https://doi.org/10.7554/eLife.00288