The laboratory is interested in the viral, cellular,and immunologic determinants of diseases induced by alphaviruses and measles virus. Alphaviruses are transmitted by mosquitoes and cause encephalitis in mammals and birds. Sindbis virus is an alphavirus that causes encephalomyelitis in mice. The outcome of Sindbis virus infection is determined by the virulence of the virus, the age of the mouse at the time of infection, the genetic background of the mouse and the immune response. Sindbis virus infects neurons in the brain and spinal cord and causes death of neurons and can cause fatal disease. Mature neurons are protected from induction of cell death and become persistently infected in the absence of an immune response. Antibody is a primary mechanism by which virus is cleared from the nervous system. This clearance occurs without harming the infected cells and the mechanism of this remarkable effect of antibody on intracellular virus replication is being determined. In addition, we have demonstrated that clearance of viral RNA from the central nervous system is influenced by CD8+ T cells and, in a antibody-independent model, interferon-gamma mediates the clearance of Sindbis virus from spinal cord neurons. The immune response can also contribute to fatal disease. Current studies are focused on understanding the mechanisms of viral clearance and disease enhancement by the immune system.

A second interest of the laboratory is in understanding measles virus pathogenesis with a particular focus on the development of novel vaccines and understanding how the virus induces immunosuppression. Monocytes, epithelial cells, and endothelial cells are infected with virus during measles. However, there are dramatic abnormalities in T cell function. Immune suppression and immune activation in response to measles virus infection are investigated at a study site at the University Teaching Hospital in Lusaka, Zambia. In Zambia, we are also examining the effect of HIV infection on measles and measles virus immunization and the effect of measles on HIV. The lab is identifying the major mechanisms of measles virus clearance and developing novel approaches to stimulate protective immunity without enhancing disease, as was seen with a formalin-inactivated vaccine in the 1960s. New cDNA and virus-vectored vaccines for measles are under development using a rhesus macaque model for measles and measles immunization.

Zilliox MJ, Parmigiani G, Griffin DE. (2006) Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens. Proc. Natl. Acad. Sci. USA In Press [PubMed]

Burdeinick-Kerr, R. and Griffin DE. (2005) Gamma interferon-dependent, noncytolytic clearance of sindbis virus infection from neurons in vitro. J. Virol. 3(1):77-84 [PubMed]

Pan, C-H, Valsamakis, A., Colella, T., Nair, N., Adams, RJ, Polack, FP, Greer, CE, Perri, S Polo, JM and Griffin DE. (2005) Modulation of disease, T cell responses and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles. Proc. Natl. Acad. Sci. USA 170:4273-80 [PubMed]

Binder, G. K., and D. E. Griffin. (2005) Interferon-gamma-mediated site-specific clearance of alphavirus from CNS neurons. Science 89:2203-2209 [PubMed]

Griffin, DE. (2003) Immune responses to virus infections of the central nervous system. Nat. Rev. Immunol. 9(6):835-43 [PubMed]

Polack FP, Hofffman, SJ, Crujeiras, G and Griffin DE. (2003) A role for nonprotective complement fixing antibodies with low avidity for measles virus in atypical measles. Nature Medicine 19(1)145-156 [PubMed]

Moss, W.J., Ryon, J.J., Monze, M., Cutts, F., Quinn, T.S. and Griffin, D.E. (2002) Suppression of HIV replication during acute measles. J. Infect. Dis. 61(9):3689-3697 [PubMed]

Permar, S., Moss, W.J., Ryon, J.J., Monze, M., Cutts, F., Quinn, T., and Griffin, D.E. (2001) Prolonged measles virus shedding in HIV-infected children detected by reverse transcriptase-polymerase chain reaction. J. Infect. Dis. 60:3569-76 [PubMed]

Polack, F. P., S. H. Lee, S. Permar, E. Manyara, H. G. Nousari, Y. Jeng, F. Mustafa, A. Valsamakis, R. J. Adams, H. L. Robinson, and D. E. Griffin. (2000) Successful DNA immunization against measles: neutralizing antibody against either the hemagglutinin or fusion glycoprotein protects rhesus macaques without evidence of atypical measles. Nature Medicine 4(3):194-203 [PubMed]