Description of Research Expertise

Research Interests
Mechanisms of HIV persistence and immune dysregulation, identification of viral and cellular determinants regulating HIV-induced apoptosis, immune suppression and latency
Molecular mechanisms of lymphocyte activation

Research Description
The Finkel lab focuses on molecular mechanisms of lymphocyte activation in health and disease, with an emphasis on mechanisms of viral persistence and immune dysregulation. Current goals include identification and mechanistic dissection of viral and cellular gene products regulating apoptosis, immune suppression and viral latency. To this end, the Finkel lab has demonstrated that the HIV surface protein, gp120, primes T cells for cell death by apoptosis. These results suggest a mechanism for the massive CD4 T cell depletion in AIDS, particularly in the face of concurrent infection and antigenic challenge with other organisms. Subsequent in vivo studies showed that this apoptosis occurs predominantly in healthy bystander cells and only rarely in infected cells, suggesting that HIV encodes or induces expression of survival genes. Using a variety of molecular techniques including microarray and gene silencing, we have identified known and novel cellular gene products that may regulate T cell apoptosis and latency in HIV infection. Pre-clinical studies are underway to test candidate drugs that may prevent or reverse HIV latency. In other studies defining signaling mechanisms of healthy lymphocytes, we showed that T cells, like some non-immune cells, use the cytoskeleton to transduce activating signals. Current work uses human blood cells and genetically engineered animals to address mechanisms of initiation of T cell activation. A novel artificial membrane system has been developed that closely mimics the cell surface and, in conjunction with real-time digital immunofluorescence microscopy, provides a valuable research tool to study the immune synapse. Finally, we are using animal models, in conjunction with dual photon laser microscopy, to develop novel therapies for autoimmune and infectious disease, including non-myeloablative bone marrow transplantation for lupus, and immune adjuvants for DNA vaccination against agents of bioterror.

Rotation Projects for 2006-2007
Testing of pro-apoptotic lentiviral vector gene therapy, using TAT-inducible small hairpin RNA (shRNA) to target survival proteins in HIV infection

Characterization of anti-apoptotic gene products identified from chronically HIV infected cells by suppression subtractive hybridization

Determine the role of reactive oxygen species in HIV-induced T-cell apoptosis

Determine the mechanism of the anti-apoptotic protein, DDIT4, in HIV-infected T-cell survival

Lab personnel:
Jiang-Fang Wang - Senior Research Associate
Mark Ma - Research Assistant Professor
Debra Shivers - Senior Research Technician