Human cytomegalovirus (HCMV), a herpesvirus, is the leading cause of congenital viral disease and a major cause of infectious disease and mortality after transplantation. Primary infection is generally followed by a prolonged period of latency; emergence from latency and recurrent disease frequently occurs with impaired immunity or immunosuppression. HCMV infections further depress immune functions. The mechanisms responsible for induction and maintenance of latency, for reactivation and for HCMV immunosuppressive actions are poorly understood. This project examines a number of the early events involved in productive and latent infections of human cells by disease- associated HCMV strains and addresses the mechanisms involved in the immunosuppressive actions of the virus on monocyte/macrophage functions. The receptor(s) used by low-passage disease-associated and laboratory HCMV strains to productively and latently infect cells will be characterized. Preliminary studies document our ability to detect HCMV receptors. The HCMV receptor(s), if protein in nature, will be isolated, biochemically characterized and molecularly cloned. The cDNA will be used to probe receptor function and expression. Processes mediating internalization of HCMV strains into cells which can be productively or latently infected will be determined. Since HCMV coexists with Ab and complement (C) in vivo and is likely coated with these reactants, the fate and possibility of altered infectivity of Ab and/or C coated HCMV interacting with Fc and C receptors on monocytes and differentiated and activated monocytes will be examined. We will also explore the modulatory influences of other cell types and cytokines on the type and characteristics of HCMV infection of monocytes/macrophages and address the mechanisms involved in molecular terms. Studies including our own have implicated the monocyte in the immunosuppression characteristic of HCMV infections. The suppressive effects of low passage clinical strains of HCMV on both immunoregulatory and inflammation-related actions of monocytes and differentiated and activated monocytes will be examined and mechanisms analyzed. Modulation of these properties by cytokines originating from HCMV infected cells will also be analyzed; where feasible it will be determined whether regulation is at the level of transcription. These studies will contribute to the understanding of the pathogenesis of HCMV productive and latent infections and the mechanisms responsible for the immunosuppressive actions of HCMV on monocyte/macrophage functions. Such information will also hopefully suggest therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025016-04
Application #
3138316
Study Section
Experimental Virology Study Section (EVR)
Project Start
1987-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Compton, T; Nowlin, D M; Cooper, N R (1993) Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology 193:834-41
Compton, T; Nepomuceno, R R; Nowlin, D M (1992) Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology 191:387-95
Cooper, N R; Nowlin, D; Taylor, H P et al. (1991) Cellular receptor for human cytomegalovirus. Transplant Proc 23:56-9, discussion 59
Nowlin, D M; Cooper, N R; Compton, T (1991) Expression of a human cytomegalovirus receptor correlates with infectibility of cells. J Virol 65:3114-21
Cooper, N R; Bradt, B M; Rhim, J S et al. (1990) CR2 complement receptor. J Invest Dermatol 94:112S-117S
Taylor, H P; Cooper, N R (1990) The human cytomegalovirus receptor on fibroblasts is a 30-kilodalton membrane protein. J Virol 64:2484-90
Cannon, M J; Pisa, P; Fox, R I et al. (1990) Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice. J Clin Invest 85:1333-7
Taylor, H P; Cooper, N R (1989) Human cytomegalovirus binding to fibroblasts is receptor mediated. J Virol 63:3991-8
Buchmeier, N A; Cooper, N R (1989) Suppression of monocyte functions by human cytomegalovirus. Immunology 66:278-83
Cooper, N R; Nemerow, G R (1989) Complement and infectious agents: a tale of disguise and deception. Complement Inflamm 6:249-58

Showing the most recent 10 out of 12 publications