Herpes Simplex Virus Pathogenesis
Herpesviruses, and especially herpes simplex virus (HSV), are among the most successful human pathogens. Herpesviruses have evolved diverse strategies to evade the host immune response, which is the major factor accounting for their success. Their ability to establish a lifelong latent infection is a particularly effective immune escape mechanism, since the virus can reactivate later giving rise to recurrent disease and a source of virus that can be transmitted to susceptible individuals.
We are studying HSV pathogenesis with the goal of (i) defining the role of host immunity in the development of HSV1 encephalitis (HSE), (ii) identifying immunomodulatory approaches capable of preventing or moderating HSE and herpes keratitis, another disease involving maladapted host immune responses and (iii) defining the molecular and immunological mechanisms involved in regulating latency and reactivation. This knowledge will facilitate rational approaches for control of recurrent HSV infections. Current projects in the laboratory are focused on determining the mechanism(s) by which pooled polyclonal human IgGs - IVIG (intravenous immunoglobulins) - exert potent anti-inflammatory, immunomodulatory and antiviral activities to protect against HSE. We are also extending these studies to other viral inflammatory diseases including West Nile virus encephalitis and pneumonia cause by highly pathogenic influenza strains such as pandemic H1N1. We have also exploited IVIG’s potent anti-viral and immunomodulatory activities to establish latent HSV infections in immunodeficient Rag mice. Importantly, we have shown that heat stress results in highly efficient synchronous in vivo reactivation culminating in high rates of HSE in these latently infected Rag mice. This powerful new latency model is being exploited to define the molecular and immunological mechanism(s) involved in regulating latency and particularly reactivation and it is ideal for screening small molecule drugs for their ability to block reactivation.
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