News and Publications

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

We study how immunosuppressive viruses can infect bone marrow cells and suppress hematopoiesis. Measles virus causes a profound cell-mediated immunosuppression that is responsible for 1 million deaths per year worldwide. Studies of infection with the virus, particularly in hematopoietic cells, indicated that measles virus can infect cells of hematopoietic lineage, beginning at the primitive CD34⁺ stem cell stage, and result in a productive infection. Infection of bone marrow stroma with measles virus inhibits hematopoiesis by preventing the ability of the stroma to support hematopoietic development and eventually destroys the stroma. 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 measles virus is cleared from the host.

In addition, our findings suggest that reagents that promote hematopoiesis may be useful for combating severe cases of measles virus-induced immunosuppression. We found that vaccine strains of measles virus can also infect CD34⁺ cells and that an engineered measles virus based on the vaccine strain can be used as a vector to deliver a reporter gene that is expressed in CD34⁺ cells, suggesting that measles virus may be a useful tool for gene therapy of stem cells.

We exploited another virus, cowpea mosaic virus (CPMV) as a nanoparticle platform for developing antivirals, vaccines, and tumor-targeting agents. The structure of the 30-nm CPMV capsid can be engineered to display therapeutic or immunogenic peptides on the surface via either genetic manipulation or chemical attachment. We developed a CPMV-based antiviral that can completely protect animals from infection and death caused by measles virus. For vaccine purposes we used the CPMV system to display antigenic peptides for generation of immune responses at mucosal surfaces such as the respiratory and gastrointestinal mucosa. In collaboration with J. Johnson and A. Schneemann, Department of Molecular Biology, and M.G. Finn, Department of Chemistry, we developed CPMV nanoparticles that are designed to target tumors. We engineered a CPMV virus that binds specifically to tumor cells in vitro. We also discovered that CPMV nanoparticles are bioavailable when given orally and that on oral administration, CPMV nanoparticles traffic intact from the gut to a variety of tissues, including lymphoid tissues, liver, kidney, blood, and brain. Preexisting antibody does not affect this trafficking, suggesting that CPMV will be a useful, orally bioavailable therapeutic nanoparticle for targeting tumors in vivo.

Publications

Hahm, B., Arbour, N., Naniche, D., Homann, D., Manchester, M., Oldstone, M.B. Measles virus infects and suppresses proliferation of T lymphocytes from transgenic mice bearing human signaling lymphocytic activation molecule. J. Virol. 77:3505, 2003.

Raja, K.S., Wang, O., Gonzalez, M.J., Manchester, M., Johnson, J., Finn, M.G. Hybrid virus-polymer materials, 1: synthesis and properties of PEG-decorated cowpea mosaic virus. Biomacromolecules 4:472, 2003.