Brian Wigdahl Professor and Chair, Microbiology and Immunology Director, Institute for Molecular Medicine and Infectious Disease Ph.D., 1980, The Medical College of Wisconsin, Milwaukee, Wisconsin 2900 Queen Lane Philadelphia, PA 19129 Tel: 215-991-8352 Fax: 215-848-2271 Email: brian.wigdahl@drexelmed.edu

Research Staff: Pooja Jain, Ph.D., Zafar Khan, Ph.D., Evelyn Kilareski, Ph.D., Michael Nonnemacher, Ph.D., Kevin Quann, Katherine Flaig
Graduate Students: Yujie Liu, Bryan Irish, Katerina Alexaki, Jonathan Pitcher, Luna Li, Anupam Banerjee, Adriano Ferruci, Sonia Shah, Benjamas Aiamkitsumrit, Saifur Rahman, Ronni Manuel, Veronique Lepoutre

Keywords:

C/EBP Factors, Genetic Variation & Gene Function, Herpes Simplex Virus Type 1, Human Immunodeficiency Virus, Human T Cell Leukemia Virus 1, Macrophages, Molecular Pathogenesis, Simian Immunodeficiency Virus, Sp Factors, Virology

Research Interests:

Retroviruses have been implicated as causative agents in immunologic dysfunction, malignancy, and a number of progressive neurologic disorders. The overall goal of the research program is to identify molecular mechanisms involved in the pathogenesis of these viral pathogens and to develop strategies to diagnose, prevent, and treat human disease caused by these devastating agents. Ongoing research is focused in three major programmatic areas utilizing molecular, cellular, and modeling technologies involving (1) protein structure and function studies using fluorescence-activated flow cytometry, laser capture and deconvolution fluorescence microscopy, (2) molecular genomics and proteomic strategies, (3) DNA sequencing and genotype analyses, (4) molecular modeling strategies to facilitate design of novel therapeutic agents, (5) DNA-protein biochemistry, (6) methods to assess transcriptional control mechanisms, (7) in vitro cell culture models, (8) viral replication studies utilizing biocontainment safety level 3 (BSL-3) facilities, (9) in vivo animal model systems, and (10) xenografting, cellular trafficking, and quantitative assessment procedures to identify specific uninfected and infected cell populations.

In the first programmatic area, the molecular mechanisms involved in regulating gene expression of human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS) and the progressive neurologic disorder, HIV-dementia (HIVD), is under exploration. Specifically, the laboratory focuses on the impact of retrovirus genetic variation, signaling pathways, cellular differentiation processes and viral transactivators on critical DNA-protein interactions involved in regulating HIV transcription in cells of monocyte-macrophage origin, including CD34+ precursor cells in the bone marrow and peripheral blood. In addition to defining the transcription regulatory mechanisms that may be critical to the etiology of HIVD, studies are also focused on defining signature sequences in the viral long terminal repeat (LTR) and genes encoding HIV regulatory proteins (Tat and Vpr) that may provide information useful in developing predictive tools to track the development of neurologic disease and therapeutic targets.

In the second area of investigation, molecular modeling strategies and other experimental approaches are being used to develop therapeutic strategies to prevent sexual transmission of HIV. These studies have led to the identification of a family of compounds that interfere with the interaction of HIV-1 gp120 with the receptor (CD4) and the coreceptors (CXCR4 and CCR5).

HTLV-1 Tax Nucleocytoplasmic Shuttling

Selected Publications:

1. Grant, C., Nonnemacher, M., Jain, P., Pandya, D., Irish, B., Williams, S. C., and B. Wigdahl.  CCAAT/enhancer-binding proteins modulate human T cell leukemia virus type I long terminal repeat activation.  Virology, 348(2): 354-369, 2006.

2. Ahuja, A, Kampani, K., Datta, S., Wigdahl, B., Flaig, K. E., and P. Jain.  Use of human antigen presenting cell gene array profiling to examine the effect of human T-cell leukemia virus type 1 Tax on primary human dendritic cells.  Journal of NeuroVirology, 12(1): 47-59, 2006.
   

3. Yao, J., Grant, C., Harhaj, E., Nonnemacher, M., Alefantis, T., Martin, J., Jain, P. and B. Wigdahl.  Regulation of human T cell leukemia virus type I gene expression by Sp1 and Sp3 interaction with TRE-1 repeat III.  DNA and Cell Biology, 25(5): 262-276, 2006.
   

4. Rando, R. F., Obara, S., Osterling, M. C., Mankowski, M., Miller, S. R., Ferguson, M. L., Krebs, F. C., Wigdahl, B., Labib, M., and H. Kokubo.  Critical design features of phenyl carboxylate-containing polymer microbicides.  Antimicrobial Agents and Chemotherapy, 50(9): 3081-3089, 2006.

5. Grant, C., Nonnemacher, M., Irish, B., Alefantis, T., and B. Wigdahl.  AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation.  Journal of Leukocyte Biology, 80: 21-39, 2006.

6. Kampani, K., Quann, K., Ahuja, J., Wigdahl, B., and P. Jain.  A novel high throughput quantum dot-based fluorescence assay for the quantitation of virus binding and attachment.  Journal of Virological Methods, 141(2): 125-132, 2007.

7. Jain, P., Ahuja, J., Khan, Z. K., Shimizu, S., Meucci, O., Kampani, K., Jennings, S., and B. Wigdahl.  Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1.  Journal of Leukocyte Biology, 82(1): 44-56, 2007.

8. Manuel, S. L., Rahman, S., Wigdahl, B., Khan, Z. K., and P. Jain.  Dendritic Cells in Autoimmune Diseases and Neuroinflammatory Disorders.  Frontiers in Bioscience, 12: 4315-4335, 2007.

9. Alexaki, A., Quiterio, S., Liu, Y., Irish, B., Kilareski, E., Nonnemacher, M., and B. Wigdahl.  PMA-induced differentiation of a bone marrow progenitor cell line activates HIV-1 LTR-driven transcription.  DNA and Cell Biology, 26(6): 387-394, 2007.

10. Alefantis, T., Flaig, K. E., Widgahl, B., and P. Jain.  Interaction of HTLV-1 Tax protein with the calreticulin: Implication for Tax nuclear export and secretion. Biomedicine and Pharmacotherapy, 61(4): 194-200, 2007.

11. Ahuja, J., Lepoutre, V., Wigdahl, B., Khan, Z. K., and P. Jain.  Induction of proinflammatory cytokines by human T cell leukemia virus type 1 Tax protein as determined by multiplexed cytokine protein array analyses of human dendritic cells.  Biomedicine and Pharmacotherapy, 61: 201-208, 2007.

12. Pandya, D., Rahman, S., Wigdahl, B., Khan, Z. K. and P. Jain.  New insights into the pathogenesis, diagnosis, and treatment of human T cell leukemia virus type 1-induced disease.  Future Virology, 2: 481-493, 2007.

13. Alexaki, A., Banerjee, A., Kilareski, E., Nonnemacher, M. R., and B. Wigdahl.  IL-1β production by differentiating TF-1 bone marrow progenitor cells.  Proceedings of the 8th International Congress of Neuroimmunology, 353-359, 2007.

14. Irish, B. P., Nonnemacher, M. R., and B. Wigdahl.  Genetic Variation and HIV-induced neurologic disease.  In “Microbial Infections of the Neurologic System” in the series, “Infections Agents and Pathogenesis.”  Edited by:  A. Seyfang, H. Friedman, and M. Bendinelli.  Springer Publishers, invited review, in press, 2007.

15. Jain, P., Mostoller, K., Flaig, K., Ahuja, J., Lepoutre, V., Alefantis, T., Khan, Z. K., and B. Wigdahl.  Identification of HTLV-1 Tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein.  Journal of Biological Chemistry, 282: 34581-34593, 2007.