News and Publications

Viruses as Tools for Understanding Pathogenesis and for Developing Antivirals, Vaccines, and Antitumor Agents

M. Manchester, G. Destito, D.S. Eto, M. Estrada, M.J. Gonzalez, I.W. Khor

We investigated the use of 2 different receptors, the human complement regulatory protein CD46 and the human lymphocyte activation marker SLAM. Each of these receptors mediates entry of measles virus into host cells and also participates in signaling cascades that have pathogenic consequences for the cells.

Studies of entry of measles virus, particularly in hematopoietic cells, indicated that the virus can infect cells of hematopoietic lineage, beginning at the primitive CD34⁺ stem-cell stage, and result in a productive infection, although little direct cytopathic effects or inhibition of hematopoiesis occurs. In contrast, when stem cells are cultured in a bone marrow microenvironment along with bone marrow stromal cells, infection of the stroma by measles virus inhibits hematopoiesis. The stroma cannot support hematopoietic development and eventually is destroyed.

Infection of the bone marrow compartment and inhibition of hematopoiesis by measles virus may be a key mechanism for the long-term cell-mediated immunosuppression that persists for months after host clearance of the virus. In addition, our findings suggest that reagents that promote hematopoiesis may be useful for combating severe cases of immunosuppression induced by measles virus.

In collaboration with J. Johnson and A. Schneemann, Department of Molecular Biology, and M.G. Finn, Department of Chemistry, we used another virus, cowpea mosaic virus (CPMV), as a tool for developing antivirals, vaccines, and tumor-targeting agents. The structure of the CPMV capsid can be engineered to display peptides on the surface via either genetic manipulation or chemical attachment. We found that display of a peptide on CPMV that competitively inhibits the interaction between measles virus and the receptor CD46 effectively inhibited measles virus infection both in vitro and in an in vivo mouse model of measles virus encephalitis, completely protecting animals from death. We expanded the CPMV system to include display of antigenic peptides for generation of immune responses in vivo, particularly by immunization at mucosal surfaces such as the respiratory and gastrointestinal mucosa. Our recent evidence indicates that CPMV particles are highly stable in the gastrointestinal tract and traffic intact from the gut to a variety of tissues, including lymphoid tissues. Together these studies indicate that using the CPMV platform to develop novel vaccines and antivirals will meet with further success.

PUBLICATIONS

Khor, I.W., Lin, T., Langedijk, J.P., Johnson, J.E., Manchester, M. Novel strategy for inhibiting viral entry by use of a cellular receptor-plant virus chimera. J. Virol. 76:4412, 2002.

Manchester, M., Smith, K.A., Eto, D.S., Perkin, H.B., Torbett B.E. Targeting and hematopoietic suppression of human CD34⁺ cells by measles virus. J. Virol. 76:6636, 2002.