The goal of this project is to determine the viral mechanisms involved in cytomegalovirus (CMV)-accelerated transplant vascular sclerosis (TVS), which is the hallmark vascular disease associated with chronic rejection of solid organ grafts. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of transplant vascular sclerosis (TVS) and vascular restenosis following angioplasty, as well as atherosclerosis. We have developed a rat heart transplant chronic rejection model that exhibits all of the hallmarks of TVS in humans. Studies by our group and others have shown that rat CMV (RCMV) infection significantly accelerates both the development of TVS as wellas chronic rejection in the rat heart allograft model. We have observed that similar to what is observed in the clinical setting that heart allografts from latently infected donor rats undergo acceleration of chronic rejection compared to uninfected controls. Interestingly, we have also observed that treatment with ganciclovir, which is a viral DMA polymerase inhibitor that blocks viral late gene expression, did not prevent the acceleration of TVS in RCMV latently infected allografts transplanted into sero-negative recipients. These results indicate that complete viral replication is not required for the acceleration of disease and that virus expression is restricted to CMV immediate early (IE) or early gene products. In this study, we will determine the viral load and cell types infected in the allograft. In addition, we will determine the viral genes that are expressed in the allografts from latently infected donors prior to and following transplanation and then determine whether these gene products contribute to the acceleration of TVS? To achieve these objectives we plan the following specific aims: 1. What are the RCMV latently infected cell types as well as the viral expression profile in the allograft prior to transplantation? A. What are the RCMV latently infected cell types in the donor hearts prior to transplantation? B. Which RCMV genes are expressed in the latently infected donor hearts? 2. What are the characteristics of RCMV acceleration of TVS in allografts from latently infected donors? A. What are the kinetics of TVS formation in allografts from latently infected donors? B. Does the spectrum of RCMV gene expression change in the latently infected allografts during the development of TVS in the presence of ganciclovir? 3. Which RCMV gene(s) expressed in latently infected allografts are required for the acceleration of TVS? A. Does mutation of the RCMV genes expressed in the latently infected allografts alter virus-induced acceleration of disease? B. What is the function of RCMV genes expressed in latently infected allografts?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083194-03
Application #
7329197
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Sopko, George
Project Start
2006-01-01
Project End
2010-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
3
Fiscal Year
2008
Total Cost
$299,068
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Kreklywich, Craig N; Smith, Patricia P; Jones, Carmen Baca et al. (2014) Fluorescence-based laser capture microscopy technology facilitates identification of critical in vivo cytomegalovirus transcriptional programs. Methods Mol Biol 1119:217-37
Vomaske, Jennifer; Denton, Michael; Kreklywich, Craig et al. (2012) Cytomegalovirus CC chemokine promotes immune cell migration. J Virol 86:11833-44
Orloff, S L; Hwee, Y-K; Kreklywich, C et al. (2011) Cytomegalovirus latency promotes cardiac lymphoid neogenesis and accelerated allograft rejection in CMV naive recipients. Am J Transplant 11:45-55
Meyer, Christine; Grey, Finn; Kreklywich, Craig N et al. (2011) Cytomegalovirus microRNA expression is tissue specific and is associated with persistence. J Virol 85:378-89
Caposio, Patrizia; Orloff, Susan L; Streblow, Daniel N (2011) The role of cytomegalovirus in angiogenesis. Virus Res 157:204-11
Umashankar, Mahadevaiah; Petrucelli, Alex; Cicchini, Louis et al. (2011) A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection. PLoS Pathog 7:e1002444
Botto, Sara; Streblow, Daniel N; DeFilippis, Victor et al. (2011) IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. Blood 117:352-61
Wu, Yunkou; Carney, Christiane E; Denton, Michael et al. (2010) Polymeric PARACEST MRI contrast agents as potential reporters for gene therapy. Org Biomol Chem 8:5333-8
Smith, M Shane; Goldman, Devorah C; Bailey, Alexis S et al. (2010) Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. Cell Host Microbe 8:284-91

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