Paula Cannon, Ph. D.
Human and Animal Virology

Paula Cannon, Ph.D.


              

Associate Professor
Member of USC Institute for Emerging Pathogens and Immune Diseases
E-Mail: pcannon@usc.edu
Office Location: HMR 502
Website
PIBBS Profile
PubMed
 

Research Overview

Research in the my lab is focused on viruses, stem cells, and gene therapy. The viruses that we study are HIV-1 and several biodefense related viruses, such as Ebola and Junin, that cause severe viral hemorrhagic fevers.

There are 3 major areas of research in the lab, each funded by both NIH and foundation grants:

(1) Zinc-finger nuclease editing of hematopoeitic stem cells - an anti-HIV therapy

ZFNs are are engineered DNA binding/cutting proteins that can be used to efficently knockout a targeted gene. My group has developed the techniques to perform this genome editing with high efficiency in human hematopoeitic stem cells (HSC), and we are currently developing this technology as an anti-HIV gene therapy by targeting the CCR5 gene.

CCR5 is the major entry co-receptor used by HIV-1 and CCR5 inhibitors are an important new class of anti-viral drugs. In addition, the recent finding that transplantation of HSC from a CCR5-negative donor to an HIV-infected patient has effectively cured him of his infection has highlighted the potential of gene/stem cell therapies that target CCR5. Using ZFNs, we are able to knockout the CCR5 gene at high levels in human HSC. We evaluate the function of such ZFN-treated HSC by transplantation into a mouse model of human hematopoiesis, where ZFN-modified HSC retain the ability to engraft and differentiate into multiple hematopoietic lineages that maintain high rates of CCR5 disruption. When we challenge the transplanted or 'humanized' mice with HIV-1, we find that the mice receiving the ZFN-treated HSC are able to effectively block HIV replication and to preserve normal levels of human T cells.

These observations suggest that ZFN tretament of a patient's own stem cells could be used as a clinical approach to tretaing HIV disease. Together with a team of scientists and clinicians at City of Hope and Sangamo Biosciences, we have been awarded a "Disease Team" grant from the Califronia Institute for Regenerative Medicine (CIRM) to enable us to develop this stem cell therapy into a clinical trial.

Link to LA Times story

(2) HIV release from cells and tetherin restriction

The release of virions from the surface of infected cells is the final stage in the HIV-1 life cycle and could be targeted for intervention, since any means of reducing the viral load in patients could significantly slow progression to AIDS. However, no drugs are currently available that block these events. Mammalian cells are know to express a variety of 'restriction factors' that inhibit virus replication, and one recently identifed factor is the BST-2 or "tetherin" protein, which acts to prevent the release of enveloped viruses from the surface of infected cells. Successful viral pathogens often express factors that block the action of restriction factors, and tetherin is known to be inhibited by the HIV-1 Vpu protein, the KSHV K5 protein and the Ebola virus GP protein. The widespread and diverse nature of anti-tetherin factors suggests that the ability to overcome tetherin restriction is of high importance for the replication of enveloped viruses.

We hypothesize that blocking the action of anti-tetherin factors such as Vpu could represent a novel strategy to combat HIV-1 replication, since this would allow the natural anti-viral activity of tetherin to be reactivated. To this end, we are studying how different anti-tetherin factors work, and also undertaking high throughput screens to search for compounds that could block the activity of viral anti-tetherin proteins.

(3) Viral hemorrhagic fevers

Junin virus is a New World arenavirus that causes a highly contagious and frequently fatal hemorrhagic fever spread by field rodents in parts of rural Argentina. Interest in the arenaviruses 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 enter cells and disable natural host cell defenses to promote their replication. The long-term goal is to search for inhibitors of arenavirus replication.

University of Southern California University of Southern California