This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Human cytomegalovirus (HCMV), a betaherpesvirus, is a frequent cause of life-threatening disease among immune compromised patients. HCMV is also the most common viral infection present at childbirth and a leading infectious cause of congenital anomalies. Understanding the molecular underpinnings of HCMV replication is crucial for the development of new therapies and antiviral drugs. During natural infection, HCMV routinely enters quiescent, resting cells that are poorly suited for the synthesis of viral DNA. One strategy by which HCMV achieves expression of cellular genes necessary for its replication is by manipulating the cell cycle. HCMV induces the infected cell to reenter the cell cycle from a resting, quiescent state (termed """"""""G0), and ultimately arrest at the G1/S-phase boundary. One mechanism by which HCMV stimulates cell cycle progression is by inactivation of the retinoblastoma tumor suppressor protein (pRb). We and others have shown that the HCMV protein kinase UL97 phosphorylates pRb at inactivating residues. We have also shown that during infection of quiescent cells, UL97-mediated inactivation of pRb is required for wild-type levels of viral DNA synthesis, and for the expression of certain E2F-regulated cellular genes involved in deoxynucleoside biosynthesis. When active, pRb functions to repress transcription mediated by cellular E2F transcription factors (E2Fs). When pRb is inactivated, E2Fs are free to stimulate S-phase gene expression, thus permitting expression of certain cellular genes required for viral DNA synthesis. However, E2Fs also directly upregulate other genes that make the cell more sensitive to programmed cell death and, via p14ARF, E2F activity can lead to stabilization of the p53 tumor suppressor protein. While much work has been done in the area of DNA viruses and tumor suppressor proteins, many important aspects of the interplay between HCMV and the pRb and p53 tumor suppressor pathways remain poorly understood, as does the nature of the pro-apoptotic cellular response to infection to HCMV. We hypothesize that HCMV infection stimulates high levels of E2F activity, which promotes expression of cellular genes necessary for HCMV viral DNA synthesis while also triggering a pro-apoptotic response that the virus must evade. To advance knowledge in this area we shall (i) determine the role of the UL97 kinase in pRb family pocket protein inactivation, (ii): elucidate the mechanism(s) by which certain pro-apoptotic cellular genes, such as PUMA, NOXA and BAX, are induced during infection, and (iii): define the biological relevance of p53 and E2Fs in the induction of pro-apoptotic responses of the host cell during infection.

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Louisiana State University Hsc Shreveport
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Kim, Jung Heon; Collins-McMillen, Donna; Buehler, Jason C et al. (2017) Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34+ Human Progenitor Cells. J Virol 91:
Martinez, Nicholas E; Sato, Fumitaka; Kawai, Eiichiro et al. (2015) Th17-biased ROR?t transgenic mice become susceptible to a viral model for multiple sclerosis. Brain Behav Immun 43:86-97
Kawai, Eiichiro; Sato, Fumitaka; Omura, Seiichi et al. (2015) Organ-specific protective role of NKT cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain. J Neuroimmunol 278:174-84
Stevenson, Emily V; Collins-McMillen, Donna; Kim, Jung Heon et al. (2014) HCMV reprogramming of infected monocyte survival and differentiation: a Goldilocks phenomenon. Viruses 6:782-807
Coleman, Carrie B; McGraw, Jennifer E; Feldman, Emily R et al. (2014) A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo. PLoS Pathog 10:e1003916
Fernando, Viromi; Omura, Seiichi; Sato, Fumitaka et al. (2014) Regulation of an autoimmune model for multiple sclerosis in Th2-biased GATA3 transgenic mice. Int J Mol Sci 15:1700-18
Martinez, Nicholas E; Karlsson, Fridrik; Sato, Fumitaka et al. (2014) Protective and detrimental roles for regulatory T cells in a viral model for multiple sclerosis. Brain Pathol 24:436-51
Sato, Fumitaka; Omura, Seiichi; Kawai, Eiichiro et al. (2014) Distinct kinetics of viral replication, T cell infiltration, and fibrosis in three phases of myocarditis following Theiler's virus infection. Cell Immunol 292:85-93
DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Hilbig, Lydia et al. (2014) The nuclear retention signal of HPV16 L2 protein is essential for incoming viral genome to transverse the trans-Golgi network. Virology 458-459:93-105
Sato, Fumitaka; Martinez, Nicholas E; Shahid, Maira et al. (2013) Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis. Am J Pathol 183:1390-1396

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