Alphaviruses and acute encephalitis ¡X Alphaviruses are transmitted by mosquitoes and cause encephalitis in mammals and birds. We study Sindbis virus, an alphavirus that causes encephalitis 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 apoptosis of neurons and fatal disease in young animals but not in older animals. Mature neurons are protected from induction of cell death and become persistently infected. More virulent strains of Sindbis virus kill mature neurons apparently by overcoming cellular inhibitors of apoptosis and improved virus replication. A gene on chromosome 2 is an important determinant of susceptibility to fatal encephalitis and we are working to identify this gene.

Antibody is a primary mechanism by which virus is cleared from the nervous system. This clearance occurs without harming the infected cells and we are determining the mechanism of this remarkable effect of antibody on intracellular virus replication. In addition, interferon-ƒv produced by T cells can decrease virus replication in some populations of neurons by an noncytolytic mechanism.

Measles virus, immune response suppression, atypical measles and vaccine development ¡X Measles is an important cause of childhood morbidity and mortality, partly due to increased susceptibility to other infections caused by virus-induced immune suppression. Monocytes, epithelial cells, and endothelial cells are infected with virus during measles. However, there are dramatic abnormalities in T cell function. We are studying the effect of measles virus infection, and immune activation in response to infection, on immune responses in tissue culture and in infected humans and rhesus macaques.

In Zambia, we have also examined the effect of HIV infection on measles and measles virus immunization. We have discovered that measles suppresses HIV replication and are identifying the mechanism of this suppression. A new vaccine for measles is under development using a rhesus macaque model for measles and measles immunization. This vaccine would aim to induce immunity in infants under the age of 6 months.

Molecular Microbiology and Immunology, measles, viral encephalitis, vaccines, arboviruses, alphaviruses, Sindbis virus, vaccine, immune response

American Academy of Microbiology

National Academy of Science

Institute of Medicine

Ng, C.G., Coppens, I., Govindarajan, D., Pisciotta, J., Shulaev, V. and Griffin, D.E. Effect of host cell lipid metabolism on alphavirus replication, virion morphogenesis, and infectivity. Proc. Natl. Acad. Sci. USA 105:16326-16331, 2008.

Sutcliffe, C.G., Scott, S., Mugala, N., Ndhlovu, Z., Monze M., Quinn, T.C., Cousens, S. Griffin D.E. and Moss, W.J. Survival from 9 months of age among HIV-infected and uninfected Zambian children prior to the availability of antiretroviral therapy. Clin. Infect. Dis. 47:837-844, 2008.

Pan, C-H, Jimenez, G., Nair, N., Wei, Q, Adams, R.J., Polack, F.P., Rolland, A., Vilalta, A. and Griffin, D.E. Use of Vaxfectin with DNA vaccine encoding the measles virus hemagglutinin and fusion proteins protects juvenile and infant rhesus macaques against measles. Clin. Vaccine Immunol. 15:1214-1221, 2008.

Garcia, M. Yu, X.F., Griffin D.E. and Moss, W.J. Measles virus inhibits human immunodeficiency virus type 1 reverse transcription and replication by blocking cell-cycle progression of CD4+ T lymphocytes. J. Gen. Virol. 89:984-993, 2008.

Greene, I.P., Lee, E-Y, Prow, N., Ngwang, B. and Griffin, D.E. Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection. Proc. Natl. Acad. Sci. USA 105:3575-3580, 2008.

Pan, C-H, Nair, N., Adams, R.J., Zink, M.C., Lee, E-Y, Polack F.P., Singh M., O’Hagan, D.T. and Griffin, D.E. Dose-dependent protection against or exacerbation of disease by a polylactide glycolide microparticle-adsorbed, alphavirus-based measles virus DNA vaccine in rhesus macaques. Clin. Vaccine Immunol. 15:697-706, 2008.

Moss, W.J., Fisher, C., Scott, S., Monze, M., Ryon, J.J., Quinn, T.C., Cutts, F. and Griffin D.E. HIV type 1 infection is a risk factor for mortality in hospitalized Zambian children with measles. Clin. Infect. Dis. 46:523-527, 2008.

Scott, S., Moss, W.J., Cousens, S., Beeler, J.A., Audet S.A., Mugala, N., Quinn, T.C., Griffin, D.E. and Cutts, F.T. The influence of HIV-1 exposure and infection on levels of passively acquired antibodies to measles virus in Zambian infants. Clin. Infect. Dis. 45:1417-1424, 2007.

Nair, N., Gans, H., Lew-Yasukawal, L., Long-Wagar, A.C., Arvin, A. and Griffin, D.E. Age-dependent differences in IgG isotype and avidity induced by measles vaccine received during the first year of life. J. Infect. Dis. 196:1339-1345, 2007.

Moss, W.J., Scott, S., Mugala, N., Ndhlovu, Z., Beeler, J., Andet, S., Ngala M., Mwangala, S., Nkonga-Mwangilwa, C., Ryon, J.J., Monze, M., Kasolo, F., Quinn, T.C., Cousens, S., Griffin, D.E. and Cutts, F.T. Immunogenicity of standard-titer measles vaccine in HIV-1-infected and uninfected Zambian children: an observational study. J. Infect. Dis. 196:347-355, 2007.

Ota, M.O., Ndhlovu, Z., Oh, S.K., Piyasirisilp, S., Berzofsky, J.A., Moss, W.J. and Griffin, D.E. The hemagglutinin protein is a primary target of the measles virus-specific HLA-A2-restricted CD8+ T cell response during measles and after vaccination. J. Infect. Dis. 195:1799-1807, 2007.

Riddell, M.A., Moss, W.J., Hauer, D., Monze, M. and Griffin, D.E. Slow clearance of measles virus RNA in children after acute measles. J. Clin. Virol. 39:312-317, 2007.

Zilliox, M.J., Moss, W.J. and Griffin, D.E. Gene expression changes in peripheral blood mononuclear cells during measles. Clin. Vaccine Immunol. 14:918-923, 2007.

Burdeinick-Kerr, R., Wind, J. and Griffin, D.E. Synergistic roles of antibody and interferon in noncytolytic clearance of Sindbis virus from different regions of the central nervous system. J. Virol. 81:5628-5636, 2007.

Ng, C.C. and Griffin, D.E. Defect in acid sphingomyelinase increases susceptibility to fatal alphavirus encephalomyelitis. J. Virol. 80:10989-10999, 2006.

Zilliox, M.J., Parmigiani, G. and Griffin D.E. Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens. Proc. Natl. Acad. Sci. (USA) 103:3363-3368, 2006.

Bear, J.S., Byrnes, A.P. and Griffin, D.E. Recombinant strains of Sindbis virus with similar heparin-binding characteristics and distinct patterns of virulence. Virology 347:183-190, 2006.

Oh, S-K, Stegman, B., Pendleton, C.D., Ota, M.O., Pan, C-H, Griffin, D.E., Burke, D.S. and Berzofsky, J.A. Protective immunity provided by HLA-A2 epitopes for fusion and hemagglutinin proteins of measles virus. Virology 352:390-399, 2006.

Moss, W.J. and Griffin, D.E. Global measles elimination. Nat. Rev. Microbiol 4:900-908, 2006.

Pan, C-H, Valsamakis, A., Colella, T., Nair, N., Adams, R.J., Polack, F.P., Greer, C.E., Perri, S., Polo, J.M. and Griffin, D.E. Modulation of disease, T cell responses and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles. Proc. Natl. Acad. Sci. (USA) 102:11581-11588, 2005.

Garcia, M., Yu, X.-F., Griffin, D.E. and Moss, W.J. In vitro suppression of human immunodeficiency virus type 1 replication by measles virus. J. Virol. 79:9197-9205, 2005.