Herpes simplex virus 1 and 2 (HSV-1, 2) are important human pathogens, producing disseminated and life- threatening neonatal infections and encephalitis, for example. They also are the most common infectious cause of corneal transplant in the USA. Genital herpes infections are a major risk factor for HIV transmission, too. Acute herpes infections resolve in a matter of days, but the virus then persists for life in a dormant, latent, state in peripheral nervous system neurons. Latent virus periodically reactivates producing recrudescence of disease. Although no vaccines are available, specific antivirals for herpes simplex virus have been clinically used since 1963. Nonetheless, the ability of these viruses to persist in latent infections, in which they express no protein that can be targeted with antivirals or immune responses, has precluded to date the development of curative therapies or effective prophylaxis. Latency is thus critical to the pathology and biology of HSV-1 and poses a major challenge to the development of curative therapeutics and effective prophylaxis. Most current models propose that epigenetic regulation plays a major role during lytic and latent herpes infection. We have recently identified a novel level of epigenetic regulation of HSV-1 transcription, regulation of transcription competency. Chromatin dynamics dictate whether HSV-1 genomes are transcriptionally competent or not, whereas the expression of individual genes is then regulated in the transcriptionally competent genomes by promoter specific factors. We will now build on those studies by testing an integrative hypothesis in which the chromatin dynamics that dictate HSV-1 transcriptional competence result from the localization of the viral genomes into nuclear domains enriched in chromatin modifiers, proteins, and posttranslational modifications that favor a highly dynamic, and transcriptionally active, chromatin. We propose that it is the destruction (or lack of assembly) of these domains in neurons what favors the silencing of the viral genomes required for latency, and their neo-formation what starts the process of reactivation. Our studies are thus centered on one of the most critical aspects of herpes simplex virus biology, pathology and epidemiology. We will use the most appropriate current technologies to address a major knowledge gap, the combined roles of epigenetics and nuclear architecture in the regulation of the establishment, maintenance and reactivation of herpes virus latency.
Although acyclovir was approved by the FDA for use against herpes simplex infections back on March 29, 1982, latency has precluded curing herpes infections. Latency, which occurs in neurons, also poses a major challenge to the development of prophylactic or therapeutic vaccines. Despite many years of hard and clever work, the regulation of latency and reactivation still eludes us. This proposal tests an integrative model in which the efforts to silence the infecting virus by the infected cell are successfully counteracted by the virus in most cells. However, these efforts are not counteracted in the neurons to be latently infected, such that the persistence of the virus in the latent state is secured. Reactivation of latency would then occur when this silencing of the viral genomes is locally disrupted in the domains of the nuclei of the latently infected neuron where the latent genomes sit. This proposal tackles a major unaddressed gap in our knowledge of the pathobiology of herpes infections, thus opening a new path to explore towards the development of better therapeutics.
