VANILLOIDS AND HSV--MOLECULAR AND STRUCTURAL ANALYSIS

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The pathogenesis of herpes simplex virus (HSV) infections involves essential virus-neuuron interactions. During primary mucocutaneous infection, virus spreads from the portal of entry via retrograde axonal transport processes to sensory ganglion neurons where it can evade the immune system by establishing a non-replicating latent infection. The latently infected neuron is the reservoir of virus responsible for recurrent HSV disease. Periodically, the neuron can reactivate latent virus to a replication competent state. Reactivated virus then moves via anterograde transport processes to cutaneous sites where further replication results in recurrent infection. While antiviral drugs like acyclovir are effective at limiting viral replication, they have no effect on viral transport or latency. The failure of acyclovir to impact on latency and the emergence o drug resistant virus strains illustrate the need for new treatment modalities. It is our supposition that drugs can be developed that are designed to disrupt essential virus-neuron interactions. Using a well characterized guinea pig model of genital HSV infection we have shown that capsaicin, a vanilloid that selectively interrupts sensory neuron functions, effectively controls both primary and recurrent genital disease. Since capsaicin does not inhibit viral replication we postulate that its effects result from the disruption of essential virus-neuron interactions. In this application we propose to further explore the mechanism(s) by which vanilloids affect the pathogenesis of mucocutaneous HSV infections. Using capsaicin analogues and known receptor agonists and antagonists we will explore the role of the vanilloid receptor and associated cation channel in capsaicin's effects on HSV disease. Using fetal rat dorsal root ganglion neurons grown in a two-chamber culture system we will characterize capsaicin's effects on intraneuronal virus transport. Using recently developed molecular biological methods and the well characterized guinea pig model of genital herpes, we will examine the effects of capsaicin on the establishment and maintenance of latent infection. Using an in vivo model of ultraviolet radiation-induced reactivation we will investigate the effect of capsaicin on the reactivation of latent virus. Collectively, these studies will yield important new information about virus-neuron interactions which will facilitate the rational development of a novel class of anti-HSV drugs.