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Anthony V. Nicola, Ph.D.
 Phone: (804) 828-9730 Address: Professional Experience
Research Interests: The overall goal of the laboratory is to understand the molecular mechanisms of herpesvirus entry into host cells. Human herpesviruses cause characteristic latent infections and can be reactivated to produce recurrent disease. Herpes simplex virus (HSV), the prototype alphaherpesvirus, infects the epithelia of oral and genital mucosa and neurons of the peripheral nervous system. We demonstrated that HSV utilizes fundamentally different cellular entry pathways to enter its relevant target cells. HSV enters human epithelial cells, such as epidermal keratinocytes, via endocytosis. In contrast, HSV enters neuronal cells by direct penetration at the plasma membrane. Cell biological, biochemical, and imaging approaches are used to study how viral components interact with cellular factors to mediate successful entry and infection. Understanding of the initial events in HSV infection can aid in the development of new antiviral drugs and vaccines. This work can also shed light on aspects of normal vesicle trafficking and has implications for therapeutic targeting of herpesvirus vectors. The process of HSV entry is comprised of several sequential stages culminating in viral gene expression and replication (see below). Several approaches are used to study each event separately. Our focus is on the viral and cellular determinants of each step.
Stepwise model of HSV entry via endocytosis: 1) Binding. HSV binds to cell surface receptors such as heparan sulfate proteoglycans and gD-receptors (e.g., nectin-1 and HVEM). 2) Internalization. Intact, enveloped virions are efficiently taken up into the cell by an endocytic process. Internalization is rapid (half time of ~ 8 min) and occurs independently of the known gD-receptors. 3) Trafficking. HSV-containing vesicles are trafficked through the cytosol at ~ 3 to 20 min post-infection. Transport is independent of interaction with gD-receptors and involves host kinase activity. 4) Penetration. By ~ 30 min post-infection, the intact virus reaches a low pH compartment. The virus then loses its envelope and the capsid escapes from the endocytic pathway. Penetration requires a gD-receptor and the viral envelope glycoproteins gB, gD, and gH-gL. 5) Docking. The HSV capsid docks at the nuclear envelope and the viral DNA is released through the nuclear pore complex. 6) Gene expression. The host nucleus is the site of HSV transcription and replication. Selected Publications: Delboy, M. G. and A. V. Nicola. 2009. A pre-immediate early role for tegument ICP0 in herpes simplex virus entry. In preparation. Dollery, S. J., K. D. Lane, M. G. Delboy, D. G. Roller and A. V. Nicola. 2009. Role of the UL45 protein in herpes simplex virus entry via low pH-dependent endocytosis and its relationship to the structure and conformation of glycoprotein B. In preparation. Dollery, S. J., M. G. Delboy and A. V. Nicola. 2009. Low pH-induced conformational change in herpes simplex virus glycoprotein B. Submitted. Delboy, M. G., C. R. Siekavizza-Robles and A. V. Nicola. 2009. Herpes simplex virus tegument ICP0 is capsid-associated and its E3 ubiquitin ligase domain is important for incorporation into virions. Journal of Virology, in press. Roller, D. G., S. J. Dollery, J. L. Doyle, and A. V. Nicola. 2008. Structure-function analysis of herpes simplex virus glycoprotein B with fusion-from-without activity. Virology 382: 207-16. Delboy, M. G., D. G. Roller, and A. V. Nicola. 2008. Cellular proteasome activity facilitates herpes simplex virus entry at a postpenetration step. Journal of Virology 82: 3381-90. (Featured in JVI Spotlight). Delboy, M. G., J. L. Patterson, A. M. Hollander, and A. V. Nicola. 2006. Nectin-2-mediated entry of a syncytial strain of herpes simplex virus via pH-independent fusion with the plasma membrane of Chinese hamster ovary cells. Virology Journal 3: 105. Nicola, A. V., J. Hou, E. O. Major, and S. E. Straus. 2005. Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway. Journal of Virology 79: 7609-7616. Milne, R. S. B., A. V. Nicola, J. C. Whitbeck, R. J. Eisenberg, and G. H. Cohen. 2005. Receptor-dependent, low pH independent endocytic entry of herpes simplex virus type 1. Journal of Virology 79: 6655-6663. Nicola, A. V. and S. E. Straus. 2004. Cellular and viral requirements for rapid endocytic entry of herpes simplex virus. Journal of Virology 78: 7508-7517. Nicola, A. V., A. M. McEvoy and S. E. Straus. 2003. Roles for endocytosis and low pH in herpes simplex virus entry into HeLa and Chinese hamster ovary cells. Journal of Virology 77: 5324-5332. Nicola, A. V., W. Chen and A. Helenius. 1999. Cotranslational folding of an alphavirus capsid protein in the cytosol of living cells. Nature Cell Biology 1: 341-345 Willis, S. H., A. H. Rux, C. Peng, J. C. Whitbeck, A. V. Nicola, H. Lou, W. Hou, L. Salvador, R. J. Eisenberg and G. H. Cohen. 1998. Examination of the kinetics of herpes simplex virus (HSV) glycoprotein D binding to the herpes virus entry mediator, using surface plasmon resonance. Journal of Virology 72: 5937-5947. Rux, A. H., S. H. Willis, A. V. Nicola, W. Hou, H. Lou, C. Peng, G. H. Cohen and R. J. Eisenberg. 1998. Functional region IV of glycoprotein D from herpes simplex virus modulates glycoprotein binding to the herpes virus entry mediator. Journal of Virology 72: 7091-7098. Nicola, A. V., M. Ponce de Leon, R. Xu, W. Hou, J. C. Whitbeck, C. Krummenacher, R. I. Montgomery, P. G. Spear, R. J. Eisenberg and G. H. Cohen. 1998. Monoclonal antibodies to distinct sites on herpes simplex virus (HSV) glycoprotein D block HSV binding to HVEM. Journal of Virology 72: 3595-3601. Krummenacher, C., A. V. Nicola, J. C. Whitbeck, H. Lou, W. Hou, J. D. Lambris, R. J. Geraghty, P. G. Spear, G. H. Cohen and R. J. Eisenberg. 1998. Herpes simplex virus glycoprotein D can bind to poliovirus receptor related protein-1 or herpes virus entry mediator, two structurally unrelated mediators of virus entry. Journal of Virology 72:7064-7074. Nicola, A. V., C. Peng, H. Lou, G. H. Cohen and R. J. Eisenberg. 1997. Antigenic structure of soluble herpes simplex virus (HSV) glycoprotein D correlates with inhibition of HSV infection. Journal of Virology 71: 2940-2946. Whitbeck, J. C., C. Peng, H. Lou, R. Xu, S. H. Willis, M. Ponce de Leon, T. Peng, A. V. Nicola, R. I. Montgomery, M. S. Warner, A. Soulika, L. Spruce, W. T. Moore, J. D. Lambris, P. G. Spear, G. H. Cohen and R. J. Eisenberg. 1997. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. Journal of Virology 71: 6083-6093. Nicola, A. V., S. H. Willis, N. N. Naidoo, R. J. Eisenberg and G. H. Cohen. 1996. Structure-function analysis of soluble forms of herpes simplex virus glycoprotein D. Journal of Virology 70: 3815-3822. |
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| Microbiology And Immunology 1101 East Marshall Street Richmond, Virginia 23298-0678 Phone: (804)828-9728 Fax: (804) 828-9946 |
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