The long-term objective of this project is to develop a novel intervention strategy to clear latent infections by herpes simplex virus (HSV). Latency is the most fascinating aspect of HSV biology and the most vexing aspect of HSV disease -- latency is why HSV infections have yet to be cured. The intervention strategy proposed here is: 1) Disrupt latency by antagonizing viral microRNAs (miRNAs) that we hypothesize repress "lytic" viral gene expression in latently infected neurons, using oligonucleotides that are complementary to these miRNAs (anti-miRs);2) If necessary, further disrupt latency by antagonizing host functions that help maintain latency;and 3) Irreversibly inactivate the resultin replicating HSV using the anti-HSV drug acyclovir. The R21 phase of this project is a collaborative effort of three labs.
The first aim i s to determine whether selected anti-miRs or selected viral mutations affecting miRNAs or their target sites (Coen lab) derepress lytic gene expression in mouse and rat neuron in vitro models of HSV latency (Leib and Wilson labs). Gene expression will be measured using PCR-based methods (Coen and Wilson labs). Selected mutations will also be tested for their effects on lytic gene expression in an in vivo mouse latency model (Coen lab).
The second aim i s to test whether these anti-miRs, alone or in at least additive combination with small molecule antagonists of host functions, induce reactivation in the mouse and rat in vitro models, and whether acyclovir can cure latency in such models. The R33 phase of this project (Coen lab) focuses on efforts to cure latency in vivo in a mouse model.
The third aim i nvestigates anti-miRs from Aim 2, and comparable HSV mutations for effects on derepression of gene expression in this model.
The fourth aim i s to test whether these anti-miRs and comparable mutations, alone or in at least additive combination with small molecules from Aim 2 induce reactivation in the mouse model. The fifth aim is to test whether combinations identified in Aim 4 together with acyclovir can cure latency in vivo in the mouse model. These studies will be accompanied by pharmacokinetic assays of anti-miR and compound concentrations in plasma and tissues, and assays of toxicities. The goal is to achieve cure of HSV with minimal toxicity.

Public Health Relevance

Herpes simplex virus (HSV) causes widespread disease that can be severe in some people. Current treatments do not cure HSV infections. This project proposes research to use information about how microRNAs contribute to how HSV hides out in latent infections to develop an intervention strategy that can cure HSV diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAI1-JKB-M (J5))
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Challberg, Mark D
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Harvard University
Schools of Medicine
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Jurak, Igor; Hackenberg, Michael; Kim, Ju Youn et al. (2014) Expression of herpes simplex virus 1 microRNAs in cell culture models of quiescent and latent infection. J Virol 88:2337-9
Pan, Dongli; Flores, Omar; Umbach, Jennifer L et al. (2014) A neuron-specific host microRNA targets herpes simplex virus-1 ICP0 expression and promotes latency. Cell Host Microbe 15:446-56