Interdisciplinary Training

Joshua Schiffer

"Use of Bioinformatics to Develop New Concepts in Viral Pathogenesis: A Mathematical Model of Herpes Simplex Virus-2 Pathogenesis"

Herpes simplex virus-2 (HSV-2) infection is notable for frequent sub-clinical shedding of virus in the genital mucosa, with rapid viral clearance during most shedding events. These viral dynamics are significantly influenced by the presence of exquisitely localized HSV-2 specific CD8+ T cells in the mucosa, and explain the widespread prevalence of HSV-2 in the population, and the synergy between HSV-2 and HIV-1 acquisition and transmission. Mathematical models provide critical insights into the pathogenesis of viral infections. We propose using a model of mucosal HSV-2 infection and immunity to synthesize a wide array of clinical and laboratory data into a complex and dynamic picture of HSV-2 pathogenesis. Several key parameters of HSV-2 turnover in the genital compartment will be defined, including free virus production, mucosal half-life of free virus, infected cell half-life, activated T-cell half-life, and basic reproductive number. The values identified for the parameters, the significance of variations in each parameter, and comparisons of the parameters between groups, will be used to explain phenomena relevant to HSV-2 therapeutics and prevention, and HIV-1 co-infection. The overriding hypothesis is that at the level of a single infected nerve ending, infection of enough epithelial cells to lead to clinically detectable ulceration is an extraordinarily rare event, despite the nearly constant release of virus from the neurons. This is due to precise, rapid immune clearance of infected cells. Only the enormous number of neurons simultaneously introducing low levels of HSV-2 into the genital tract favors breakthroughs of viral shedding and ulceration.