Human herpes simplex viruses (HSV-1 and HSV-2) cause significant morbidity and mortality in neonatal and immunocompromised populations. HSVs are cytolytic viruses which have profound impacts on their host cells. Consequences of HSV-1 infection of cultured cells include the induction of apoptosis and the concomitant synthesis of protein(s) which act to block this process. The broad, long-term objective of our research program is to determine the function of viral and cellular factors involved in apoptosis during HSV-1 infection of human cells. In this project, we are identifying the factors/events that trigger apoptosis during infection and the genes encoding the proteins responsible for its prevention. We showed that HSV-1 induction of apoptosis in human cells occurs in the absence of de novo viral protein synthesis. Our preliminary data indicates that viral entry is not sufficient to induce the process. In our first aim, the hypothesis which we are testing is that the initiation of viral gene expression is the trigger of apoptosis in infected human cells. We also showed that an anti-apoptotic activity is synthesized between 3 and 6 hours after HSV-1 infection of human cells. In our second aim, the hypothesis we are testing is that virally-induced factor(s) are responsible for the anti-apoptotic function. The goal of these studies is to isolate genes involved in blocking of apoptosis during infection using a combination of biochemical and molecular genetic techniques. These studies are designed to help elucidate the complexities of apoptotic programmed cell death during the replication of this important human pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048582-05
Application #
7217113
Study Section
Virology Study Section (VR)
Program Officer
Beisel, Christopher E
Project Start
2002-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
5
Fiscal Year
2006
Total Cost
$289,655
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Cotter, Christopher R; Kim, Won-keun; Nguyen, Marie L et al. (2011) The virion host shutoff protein of herpes simplex virus 1 blocks the replication-independent activation of NF-ýýB in dendritic cells in the absence of type I interferon signaling. J Virol 85:12662-72
Bowles, Robert N; Blaho, John A (2011) A truncation mutation of the neurovirulence ICP22 protein produced by a recombinant HSV-1 generated by bacterial artificial chromosome technology targets infected cell nuclei. J Neurovirol 17:559-69
Cotter, Christopher R; Nguyen, Marie L; Yount, Jacob S et al. (2010) The virion host shut-off (vhs) protein blocks a TLR-independent pathway of herpes simplex virus type 1 recognition in human and mouse dendritic cells. PLoS One 5:e8684
Blaho, John A (2010) Oncoapoptosis: a novel molecular therapeutic for cancer treatment. IUBMB Life 62:87-91
Schlegel, Elisabeth F M; Blaho, John A (2009) A conserved carboxy-terminal domain in the major tegument structural protein VP22 facilitates virion packaging of a chimeric protein during productive herpes simplex virus 1 infection. Virology 387:449-58
Nguyen, Marie L; Blaho, John A (2009) Cellular players in the herpes simplex virus dependent apoptosis balancing act. Viruses 1:965-78
Cotter, Christopher R; Blaho, John A (2009) Detection of herpes simplex virus dependent apoptosis. Methods Mol Biol 559:371-87
Lopez, Maria R; Schlegel, Elisabeth F M; Wintersteller, Sandra et al. (2008) The major tegument structural protein VP22 targets areas of dispersed nucleolin and marginalized chromatin during productive herpes simplex virus 1 infection. Virus Res 136:175-88
Bowles, Robert N; Yedowitz, Jamie C; Blaho, John A (2008) Reconsideration of viral protein immunoblotting for differentiation of human herpes simplex viruses. Diagn Microbiol Infect Dis 62:167-76
Goodkin, Margot L; Epstein, Seth; Asbell, Penny A et al. (2007) Nuclear translocation of NF-kappaB precedes apoptotic poly(ADP-ribose) polymerase cleavage during productive HSV-1 replication in corneal epithelial cells. Invest Ophthalmol Vis Sci 48:4980-8

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