Inhibition of HSV-1-associated Ocular Neovascularization by Cyclin-dependent Kinase Inhibitors

Undergraduate #100
Discipline: Biological Sciences
Subcategory: Microbiology/Immunology/Virology

Usman Chaudhry - Xavier University of Louisiana
Co-Author(s): Thomas Vu, Elise I. LeMelle, Tatyana T. Santoke, Bria Carmichael, Hasahn Conway, Sydnie Turner, Briana Jarrett, Kevin Lam, Moamen Ismail, Willie Sparkman, Ashley N. Sankey, Monique N. Westley, Eric J. Fontenot, Eric Stewart, Heba A. Sarhan, Fiyinfolu T. Mustapha, Partha S, Bhattacharjee, and Harris E. McFerrin, Xavier University of Louisiana, LA Kenneth F. Swan, Cindy B. Morris, and Deborah E. Sullivan, Tulane University, LA Konstantin G. Kousoulas, Louisiana State University, LA

---

Herpes simplex virus type 1 (HSV-1) infects greater than 90% of humans worldwide and during ocular infection produces inflammation and angiogenesis that can lead to blindness. In the United States, HSV infection is the leading cause of infectioninduced blindness; nearly 40,000 new cases are reported and 300,000 cases are treated yearly. Cyclin-dependent kinases, mostly known for their involvement in the cell cycle and transcription, are involved in HSV transcription and replication. Cyclin-dependent kinase 9 (CDK9) and its downstream target, serine 2-phosphorylated RNA polymerase II, are essential in HSV -1 transcription and replication however, to date there is little literature on the role of CDKs in HSV infection of the eye or on the efficacy of CDK inhibitors in preventing HSV-1-associated ocular neovascularization and its consequences. We are testing the hypothesis that cyclin-dependent kinase 9 inhibitors (Flavopiridol, FP and 5,6-Dichloro- 1-β-D-ribofuranosylbenzimidazole, DRB) decrease angiogenesis and clinical pathology associated with ocular HSV-1 infection. To date, we have demonstrated that these inhibitors decrease vascular endothelial cell migration, invasion, tubule formation in vitro and angiogenic factor-induced angiogenesis in chick embryo and mouse Matrigel angiogenesis models. We have further determined that FP and DRB are non-toxic in rabbit and mouse eyes, and both drugs decrease mouse corneal neovascularization, clinical severity and neutrophil invasion due to HSV-1 infection to levels observed in mice treated with an antiherpetic control drug, trifluorothymidine. Additionally, FP and DRB also reduce HSV-1 replication in culture and in the eye.

Funder Acknowledgement(s): Support from the National Institute of Health through the National Institute of General Medical Sciences Grant 8P20GM103424 is gratefully acknowledged.

Faculty Advisor: Harris McFerrin,