Anthony V. Nicola, Ph.D.
V. Nicola, Ph.D.
Assistant Professor of Virology
B.A., Drew University
Ph.D., University of Pennsylvania
Post-doctoral, Yale University and Swiss Federal Institute of Technology
are a significant cause of morbidity and mortality in humans and animals
worldwide. Herpes simplex virus (HSV) remains a major global pathogen
causing oral and genital infections, blindness, encephalitis, and neonatal
infections. The long-term goal of my laboratory is to understand the
molecular processes that herpesviruses use to gain entry into host cells.
HSV causes lifelong, latent infection for which there is no cure. A better
understanding of how HSV interacts with the cell during the initial stages
of infection will identify novel intervention strategies and antiviral drug
targets. We utilize a combination of cellular, molecular, biochemical, and
microscopic approaches to delineate the step-by-step itinerary of the
dogma that herpesviruses enter cells by fusion with the plasma membrane in a
pH-independent manner was overturned when we identified a pH-dependent
endocytic entry pathway for HSV into epithelial cells. It is now appreciated
that herpesviruses utilize acid-dependent pathways in a cell-specific
manner. Our current research focuses on the virus-cell interactions needed
for two sequential steps in the initiation of infection: penetration of the
genome-containing capsid into the cytoplasm and transport of the capsid to
the nucleus, the site of herpesviral DNA replication. My lab has shown that
to accomplish these steps, HSV engages the two distinct machineries of
intracellular degradation: the low pH endosomal-lysosomal pathway and the
26S proteasome system.
Model of the role of the cellular degradation machinery in the initiation of
HSV infection. For illustration, nonendocytic (A) and endocytic (B) pathways
are shown in a single cell. In neurons (A), the capsid penetrates directly
at the plasma membrane. In mucosal epithelial cells (B), HSV is taken up by
a lysosome-terminal endosomal pathway. The normal, low pH environment of an
endosome serves as a cue for HSV to escape prior to lysosomal degradation.
The mildly acidic pH of ~ 5.8 triggers conformational change in envelope
glycoprotein B (gB), which is needed for membrane fusion and penetration of
the capsid into the cytosol. Regardless of pathway (A, B), the penetrated
capsid requires active proteasomes for transport to the nuclear envelope.
The virion protein ICP0, which is present in the tegument layer, regulates
the proteasome-dependent delivery of capsids.
Dollery, S. J., M. G. Delboy, and A. V. Nicola. 2010. Low
pH-induced conformational change in herpes simplex virus glycoprotein B.
Journal of Virology 84: 3759-3766.
Delboy, M.G., C. R. Siekavizza-Robles and A. V. Nicola. 2010.
Herpes simplex virus tegument ICP0 is capsid-associated and its E3 ubiquitin
ligase domain is important for incorporation into virions. Journal of
Virology 84: 1637-1640.
Siekavizza-Robles, C. R., S. J. Dollery and A. V. Nicola. 2010.
Reversible conformational change in herpes simplex virus glycoprotein B with
fusion-from-without activity is triggered by mildly acidic pH.
Virology Journal 7: 586.
Delboy, M. G. and A. V. Nicola. 2011. A pre-immediate early role
for tegument ICP0 in the proteasome-dependent entry of herpes simplex virus.
Journal of Virology 85: 5910-5918. Featured in JVI Spotlight.
Dollery, S. J., C. C. Wright, D. C. Johnson and A. V. Nicola. 2011.
Low pH-dependent changes in the conformation and oligomeric state of the
pre-fusion form of herpes simplex virus glycoprotein B are separable from
fusion activity. Journal of Virology 85: 9964-9973.