Molecular Virology and Experimental Therapeutics laboratory

Research aims include:

• Characterize receptor engagement, membrane fusion, and cell entry of measles virus
• Understand tropism, and the mechanisms of virulence and immunosuppression
• Re-target tropism, and develop vectors for oncolytic therapy of lymphoma
• Develop vaccines protecting against measles and the hepatitis B or the hepatitis C virus

Approach

Unifying scientific principles in biochemistry, molecular and cell biology, and genetics have often been discovered in viral systems. Viruses know how to take control of cells. My laboratory studies the small RNA virus that causes measles, and related viruses. We have characterized mechanisms of receptor attachment and cell entry, and post-entry processes that this virus has developed to trasform a cell in a factory producing almost exclusively its progeny.

Pathogenic (wild type) measles virus targets SLAM (signaling lymphocytic activation molecule), a receptor¹ expressed by activated immune cells, starting a blazing infection of the immune system. The live-attenuated vaccine strain recognizes also the ubiquitous protein CD46, and is less virulent. We have mapped on the viral attachment protein (hemagglutinin) the footprints not only of the two known viral receptors, but also of the unknown epithelial cell receptor, which we seek to identify. We are also characterizing the dynamics of the molecular interactions that sustain membrane fusion. We do this by mutagenizing the two viral envelope proteins (hemagglutinin and fusion proteins), and the receptors.

Measles is the disease with which virus-induced immunosuppression² was discovered in 1908. We are characterizing how three viral proteins (P, V and C) control innate immunity by interacting with different cytoplasmic proteins like the signal transducer and activator of transcription protein STAT1, and the RNA helicase mda-5. To characterize the mechanisms of virulence and attenuation, we generate viruses unable to interact selectively with one of these proteins, and infect first genetically modified mice and then fully susceptible hosts (monkeys).

Based on the safe and effective live attenuated measles vaccine strain we develop divalent vaccines³ to protect humans against measles and additional pathogens like the hepatitis B or the hepatitis C viruses. These vectored measles viruses would deliver an additional immunization safely and without additional costs. We have shown that a vector expressing the hepatitis B surface antigen induces protective levels of antibodies while protecting rhesus monkeys against measles challenge. We are generating vectors with the potential of inducing strong hepatitis C virus humoral and cellular immune responses.

We are also reprogramming the measles vaccine strain into an oncolytic vector⁴ that selectively eliminates cancer cells. We have developed a three-layer targeting strategy encompassing tumor-specific activation of viral particles, targeted cancer cell entry, and cancer cell specific replication. Moreover we have armed viruses with prodrug convertases or cytokines. We shield measles virus from neutralizing antibodies, frequently available in cancer patients, by recoating it with the envelopes of non-cross reacting related viruses. To assess efficacy we operate with human tumors set in immunodeficient mice, and also with a fully immunocompetent tumor model. The main target of oncolysis is lymphoma, in particular mantle cell lymphoma.

1. Leonard, V.H.L., Sinn, P.L., Hodge, G., Miest, T., Devaux, P., Oezguen, N., Braun, W., McCray, P.B., McChesney, M.B., Cattaneo, R. Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. J Clin Invest. 2008 Jul;118(7):2448-58. (see also COMMENTARY J Clin Invest. 2008 Jul;118(7):2386-9.)
2. Devaux, P., Hodge, G., McChesney, M.B., Cattaneo, R. Attenuation of V- or C- defective measles viruses: infection control by the inflammatory and interferon responses of rhesus monkeys. J Virol. 2008 Jun;82(11):5359-67. Epub 2008 Apr 2.
3. Reyes del Valle, J., Devaux, P., Hodge, G., Wegner, N.J., McChesney, M.B., Cattaneo, R. A vectored measles virus induces hepatitis B surface antigen antibodies while protecting macaques against measles challenge. J Virol. 2007 Oct;81(19):10597-605. Epub 2007 Jul 18. (see also SPOTLIGHT p. 10208)
4. Cattaneo, R., Miest, T., Shashkova, E.V., and Barry, M.A. Reprogrammed viruses as cancer therapeutics: targeted, armed, and shielded. Nat Rev Microbiol. 2008 Jul;6(7):529-40.