This proposal uses the guinea pig as a model for the study of cytomegalovirus (CMV) infections in humans. The major emphasis of the project has been placed on elucidating, in guinea pigs, CMV induced pathogenic processes that are of clear clinical relevance to human CMV infections. These include infections associated with the mononucleosis syndrome, infections associated with interstitial pneumonia, infections of pregnant hosts and congenital infections. The research plan has been designed to elucidate in these disease entities (1) the state of the viral genome in tissues of acutely and chronically infected guinea pigs; (2) the cell populations that carry the viral genome and/or viral gene transcripts; and (3) the host defense mechanisms that participate in recovery from acute virus spread and in maintenance of CMV persistence. In addition to studies of mononucleosis syndrome and of interstitial pneumonia, the proposal includes experiments that will explore mechanisms of CMV reactivation during pregnancy, of transplacental CMV transfer and of congenital CMV infections following acquisition of CMV infection at various stages of gestation. The presence of infectious virus, viral antigen, viral genome and viral gene transcripts will be assessed in tissues obtained from acutely and persistently infected guinea pigs. Detection of guinea pig CMV-DNA and RNA transcripts will be carried out by in situ hybridization with whole genomic or subgenomic probes prepared from cloned fragments of guinea pig CMV-DNA. Specific cell populations will be identified by immunocytochemistry or histochemistry using available antigenic or enzyme markers. Experiments involving depletion, in vivo, of specific cell populations with monoclonal antibodies, or cell transfers of unseparated and selectively depleted cell populations will be initiated to investigate cellular elements operative in recovery from acute CMV infection and in maintenance of CMV persistence. The information obtained is expected to determine the presence of viral DNA and RNA in specific cells during acute and persistent CMV infections. In addition, virus host interactions at the local and systemic levels and mechanisms involved in the establishment of persistent infections will be elucidated. Considerable insight will be gained into important questions related to human CMV infections including transplacental transmission, mechanisms of reactivation and host defense processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD010609-13
Application #
3311339
Study Section
Experimental Virology Study Section (EVR)
Project Start
1979-06-01
Project End
1991-09-30
Budget Start
1989-04-01
Budget End
1991-09-30
Support Year
13
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Griffith, B P; Aquino-de Jesus, M J (1991) Guinea pig model of congenital cytomegalovirus infection. Transplant Proc 23:29-31, discussion 31
Griffith, B P; Chen, M; Isom, H C (1990) Role of primary and secondary maternal viremia in transplacental guinea pig cytomegalovirus transfer. J Virol 64:1991-7
Griffith, B P; Isom, H C; Lavallee, J T (1990) Cellular localization of cytomegalovirus nucleic acids in guinea pig salivary glands by in situ hybridization. J Virol Methods 27:145-57
Bu, F R; Griffith, B P (1990) Immunoblot analysis of the humoral immune response to cytomegalovirus in non-pregnant and pregnant guinea pigs. Arch Virol 110:247-54
Aquino-de Jesus, M J; Griffith, B P (1989) Cytomegalovirus infection in immunocompromised guinea pigs: a model for testing antiviral agents in vivo. Antiviral Res 12:181-93
Sha, M; Griffith, B P; Raveh, D et al. (1987) Detection of guinea pig cytomegalovirus nucleic acids in cultured cells with biotin-labelled hybridization probes. Virus Res 6:317-29
Fong, C K; Cohen, S D; McCormick, S et al. (1987) Antiviral effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine against cytomegalovirus infection in a guinea pig model. Antiviral Res 7:11-23
Markham Jr, D F; Griffith, B P; Lerner, E et al. (1987) Effects of cyclosporine on chronic cytomegalovirus infection in the guinea pig. Intervirology 28:171-80
Zheng, Z M; Lavallee, J T; Bia, F J et al. (1987) Thymic hypoplasia, splenomegaly and immune depression in guinea pigs with neonatal cytomegalovirus infection. Dev Comp Immunol 11:407-18
Goff, E; Griffith, B P; Booss, J (1987) Delayed amplification of cytomegalovirus infection in the placenta and maternal tissues during late gestation. Am J Obstet Gynecol 156:1265-70

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