Education:
BSc 1984 Microbiology- University of Liverpool, UK
PhD 1990 Genetics- University of Liverpool, UK
Postdoctoral Research Fellowship:
1992-1996 University of Oxford, United Kingdom
1990-1992 Harvard Medical School, Boston, Massachusettes
Started at USC: 1996
Research Topics: Virology, Gene Therapy, Gene Regulation/Transcription
Research Description
My group is interested in understanding how enveloped RNA viruses enter and exit host cells. These are critical steps in the virus life cycle and represent important targets for drug development. The viruses that we are currently studying include HIV, the causative agent of AIDS, and the family of pathogenic arenaviruses typified by Junin virus, which causes Argentine Hemorrhagic Fever.
Recently, there has been much progress in our understanding of how HIV is released from an infected host cell. This is an important aspect of the virus life cycle to target for intervention, as any means of reducing the viral load in patients will significantly slow progression to AIDS, yet no drugs are currently available that block this event. My group is studying the role played in this event by the HIV-1 accessory protein, Vpu, and its counterpart in HIV-2, which turns out to be the envelope (Env) protein. We have identified the domains of the HIV-2 Env that are necessary for this effect and have demonstrated the involvement of the host's endocytosis machinery. We have also identified a mutant cell line that is not responsive to Vpu, and which is facilitating our search for the host cell pathways that are involved.
Junin virus causes a highly contagious and frequently fatal hemorrhagic fever, spread by field rodents in parts of rural Argentina. Interest in this group of viruses is growing because of the awareness that they could be developed as bioweapons and Junin has been designated by the CDC as a Category A agent. Clearly, this virus is too dangerous to work with under normal laboratory conditions. However, by using molecular tricks to create 'mix and match' or pseudotyped viruses, we can keep the features of the virus that we wish to study (such as its entry pathway), while removing the rest of the virus genome. In this way, we are investigating how these highly pathogenic viruses bind to and enter cells, and are searching for the specific cellular receptor. By understanding more about these early events, we hope to be able to devise new strategies to block virus infection.
At the same time, understanding how viruses enter cells has great implications for improving gene therapy vectors that are actually based on viruses. Here, we are striving to improve vector entry so that therapeutic genes can be delivered efficiently to enough cells in a patient's body to achieve a beneficial effect. We are particularly interested in lentiviral vectors, which are derived from HIV itself. These vectors are effective at delivering genes to hematopoietic stem cells, which makes them useful for gene therapy approaches to genetic diseases such as immune deficiencies, as well as HIV infection. These clinical applications are a key focus of the Division of Research Immunology/Bone Marrow Transplantation and the Program in Gene, Immune and Stem Cell Therapy here at CHLA. Ultimately, being able to harness a human pathogen such as HIV in order to develop tools to treat other human diseases is a sweet irony to me as a virologist.
Selected Publications
Kahl CA, Cannon PM, Oldenburg J, Tarantal AF, Kohn DB. - Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors. - Gene Ther [ 2008 ] Apr 3; . PubMed
Flanagan ML, Oldenburg J, Reignier T, Holt N, Hamilton GA, Martin VK, Cannon PM. - New world clade B arenaviruses can use transferrin receptor 1 (TfR1)-dependent and -independent entry pathways, and glycoproteins from human pathogenic strains are associated with the use of TfR1. - J Virol [ 2008 ] Jan;82(2):938-48 . PubMed
Reignier T, Oldenburg J, Flanagan ML, Hamilton GA, Martin VK, Cannon PM. - Receptor use by the Whitewater Arroyo virus glycoprotein. - Virology [ 2008 ] Feb 20;371(2):439-46 . PubMed
Weber EL, Cannon PM. - Promoter choice for retroviral vectors: transcriptional strength versus trans-activation potential. - Hum Gene Ther [ 2007 ] Sep;18(9):849-60 . PubMed
Oldenburg J, Reignier T, Flanagan ML, Hamilton GA, Cannon PM. - Differences in tropism and pH dependence for glycoproteins from the Clade B1 arenaviruses: implications for receptor usage and pathogenicity. - Virology [ 2007 ] Jul 20;364(1):132-9 . PubMed
Reignier T, Oldenburg J, Noble B, Lamb E, Romanowski V, Buchmeier MJ, Cannon PM. - Receptor use by pathogenic arenaviruses. - Virology [ 2006 ] Sep 15;353(1):111-20 . PubMed
Noble B, Abada P, Nunez-Iglesias J, Cannon PM. - Recruitment of the adaptor protein 2 complex by the human immunodeficiency virus type 2 envelope protein is necessary for high levels of virus release. - J Virol [ 2006 ] Mar;80(6):2924-32 . PubMed
Abada P, Noble B, Cannon PM. - Functional domains within the human immunodeficiency virus type 2 envelope protein required to enhance virus production. - J Virol [ 2005 ] Mar;79(6):3627-38 . PubMed
