Human-cytomegalovirus (HCMV) is a significant human pathogen. Primary infection and reactivation of HCMV causes severe diseases in neonates and immuno-compromised individuals. Previously, we have cloned HCMV strains AD 169 and Toledo as infectious bacterial artificial chromosomes (BAC), developed an efficient BAC-based HCMV genetic system and constructed a comprehensive collection of HCMV AD 169 mutants using a systematic mutagenesis scheme. Initial characterization of the HCMV mutant library has generated a body of information that allows us to start to delineate functions of many previously uncharacterized viral genes. The long term goal of this research project is to understand the mechanisms by which HCMV inhibits programmed cell death, i.e. apoptosis, in virus infection. Apoptosis is one of the critical host defenses in response to virus infection to eliminate virus replication and spread;HCMV has evolved strategies to antagonize apoptosis for its replication, persistence and dissemination in the host. Over-expressions of several HCMV proteins (i.e. IE1, IE2, pUL36 and pUL37x1) have been shown to inhibit apoptosis. We have taken advantage of the AD169 mutant library to directly identify the HCMV protein pUL38 as a novel cell death suppressor that is required for efficient virus infection in human fibroblasts. We hypothesize that pUL38 plays an important role in preventing cell death and facilitating virus replication in various cell types instrumental to HCMV pathogenesis.
In Specific Aim 1, we will define the biological role of pUL38 and its murine cytomegalovirus homolog (i.e., pM38) in virus infection in various cell culture models.
In Specific Aim 2, we will use the mutational approach to define the sequence basis for the ability of pUL38 to block cell death in virus infection.
In Specific Aim 3, we will investigate the mechanisms by which pUL38 interferes with cellular signaling pathways to block apoptosis. The proposed studies will lead to a better understanding of the complex apoptosis paradigm during CMV infection and set the stage for using the mouse model of MCMV infection as a valuable alternative to study pUL38 in CMV pathogenesis in vivo. Ultimately, these virus-encoded apoptosis suppressors have the potential to serve as candidate targets for developing novel therapeutic interventions to control this globally important pathogen.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Ogunbiyi, Peter
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Washington University
Schools of Medicine
Saint Louis
United States
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Chapa, Travis J; Du, Yushen; Sun, Ren et al. (2017) Proteomic and phylogenetic coevolution analyses of pM79 and pM92 identify interactions with RNA polymerase II and delineate the murine cytomegalovirus late transcription complex. J Gen Virol 98:242-250
Bai, Yadan; Xuan, Baoqin; Liu, Haiyan et al. (2015) Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38. J Virol 89:7625-35
Perng, Yi-Chieh; Campbell, Jessica A; Lenschow, Deborah J et al. (2014) Human cytomegalovirus pUL79 is an elongation factor of RNA polymerase II for viral gene transcription. PLoS Pathog 10:e1004350
Chapa, Travis J; Perng, Yi-Cheih; French, Anthony R et al. (2014) Murine cytomegalovirus protein pM92 is a conserved regulator of viral late gene expression. J Virol 88:131-42
Caffarelli, Nicolas; Fehr, Anthony R; Yu, Dong (2013) Cyclin A degradation by primate cytomegalovirus protein pUL21a counters its innate restriction of virus replication. PLoS Pathog 9:e1003825
Chapa, Travis J; Johnson, L Steven; Affolter, Christopher et al. (2013) Murine cytomegalovirus protein pM79 is a key regulator for viral late transcription. J Virol 87:9135-47
Fehr, Anthony R; Yu, Dong (2013) Control the host cell cycle: viral regulation of the anaphase-promoting complex. J Virol 87:8818-25
Savaryn, John P; Reitsma, Justin M; Bigley, Tarin M et al. (2013) Human cytomegalovirus pUL29/28 and pUL38 repression of p53-regulated p21CIP1 and caspase 1 promoters during infection. J Virol 87:2463-74
McKinney, Caleb; Yu, Dong; Mohr, Ian (2013) A new role for the cellular PABP repressor Paip2 as an innate restriction factor capable of limiting productive cytomegalovirus replication. Genes Dev 27:1809-20
Paredes, Anne M; Yu, Dong (2012) Human cytomegalovirus: bacterial artificial chromosome (BAC) cloning and genetic manipulation. Curr Protoc Microbiol Chapter 14:Unit14E.4

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