Dr. Joshua T Schiffer is completing Infectious Diseases fellowship and an MS degree in Epidemiology at the University of Washington in 2009. This proposal describes a 5-year training program, which will allow him to develop an independent academic career in clinical research and mathematical modeling of genital herpes simplex virus-2 (HSV-2) infection. Dr. Lawrence Corey is an internationally renowned leader in clinical HSV-2 research and is the mentor for this award. HSV-2 is the most prevalent cause of genital ulcers worldwide and has emerged as a significant risk factor for acquisition and transmission of HIV. HSV-2 transmission most frequently occurs during periods of asymptomatic genital shedding. Our group has recently used intensive sampling (swabbing the genital surfaces 4 times per day) to demonstrate that the majority of genital shedding episodes last less than 12 hours, suggesting a frequent reactivation rate from the ganglia and a brisk peripheral immune response. We recently designed a novel mathematical model of HSV replication and immune response that we fit to quantitative HSV PCR data derived from daily genital swabs performed during a genital lesion. The model was then run in a stochastic format over 365 days leading to novel hypotheses regarding pathogenesis. The goal of the current proposal is to prove several of these hypotheses by linking our model to more detailed prospectively gathered data including HSV copy number from frequent genital PCR swabs, CD8+ T-cell density from serial biopsies, and lesion size from photographs and serial measurements. We will also obtain individual parameter values for patients using experimental techniques.
Aim 1 describes our protocol for gathering this data in 20 HIV positive and 20 HIV negative participants.
In Aim 2, we propose performing biopsies before, and deriving model parameters during, successive shedding episodes in our participants. We seek to prove that CD8+ T-cell expansion will occur only during lesional shedding episodes but not during smaller low-copy shedding episodes, and that CD8+ T-cell density at episode onset inversely correlates with lesion size and peak HSV copy number.
In Aim 3, we will swab patients intensively for 60 days to determine shedding frequency, and follow clinically for a year to determine recurrence frequency. We will then use prediction models to determine model parameters predict heterogeneity in these outcomes.

Public Health Relevance

The model is novel in the modeling field based on it stochastic format, its focus on mucosal immunity, and on its tight linkage to detailed sequential quantitative virologic and immune cell data. The goal of our current funding application is to validate the model's initial prediction and parameter estimates with intensive clinical sampling of study subjects, and individualized laboratory verification of model parameters.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZAI1-AWA-M (S1))
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Challberg, Mark D
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University of Washington
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Schiffer, Joshua T; Swan, David A; Magaret, Amalia et al. (2016) Mathematical modeling of herpes simplex virus-2 suppression with pritelivir predicts trial outcomes. Sci Transl Med 8:324ra15
Mayer, Bryan T; Srinivasan, Sujatha; Fiedler, Tina L et al. (2015) Rapid and Profound Shifts in the Vaginal Microbiota Following Antibiotic Treatment for Bacterial Vaginosis. J Infect Dis 212:793-802
Melvin, Ann J; Mohan, Kathleen M; Schiffer, Joshua T et al. (2015) Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr 166:827-33
Schiffer, Joshua T; Mayer, Bryan T; Fong, Youyi et al. (2014) Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding. J R Soc Interface 11:20140160
Dhankani, Varsha; Kutz, J Nathan; Schiffer, Joshua T (2014) Herpes simplex virus-2 genital tract shedding is not predictable over months or years in infected persons. PLoS Comput Biol 10:e1003922
Matrajt, Laura; Younan, Patrick M; Kiem, Hans-Peter et al. (2014) The majority of CD4+ T-cell depletion during acute simian-human immunodeficiency virus SHIV89.6P infection occurs in uninfected cells. J Virol 88:3202-12
Schiffer, Joshua T (2013) Mucosal HSV-2 Specific CD8+ T-Cells Represent Containment of Prior Viral Shedding Rather than a Correlate of Future Protection. Front Immunol 4:209
Schiffer, Joshua T; Swan, Dave A; Stone, Daniel et al. (2013) Predictors of hepatitis B cure using gene therapy to deliver DNA cleavage enzymes: a mathematical modeling approach. PLoS Comput Biol 9:e1003131
Jing, Lichen; Schiffer, Joshua T; Chong, Tiana M et al. (2013) CD4 T-cell memory responses to viral infections of humans show pronounced immunodominance independent of duration or viral persistence. J Virol 87:2617-27
Schiffer, Joshua T; Corey, Lawrence (2013) Rapid host immune response and viral dynamics in herpes simplex virus-2 infection. Nat Med 19:280-90

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